Innopharma Module: Medical Devices

• This Innopharma Module focuses on Medical Devices, a significant and growing global industry.
• Medical devices, ranging from simple to complex, are subject to design, manufacturing, and regulation.
• The module highlights the importance of good manufacturing practice and provides an accessible online learning environment, followed by an assessment.

Course Overview and Objectives

• The course aims to provide an understanding of Quality, Regulations, and Regulatory bodies.
• Participants will learn about Good Manufacturing Practice, Regulatory Bodies, Regulations, and the Pharmaceutical Quality Management System (PQMS).
• The PQMS includes the building blocks that form the Quality System, also known as Quality System Elements.

What is Quality?

• Quality is defined as a standard measured against similar things.
• A medicinal product must contain the correct ingredients in the correct quantities and be free from contamination.
• Products should have the desired effects without harming the patient
• Products should have correct labeling and proper sealing to avoid medication errors, damage, contamination, and degradation.
• Quality assurance ensures that a drug is fit for its purpose.

History of Regulations

• In 1937, the reformulation of Sulphanilamide Elixir led to 107 deaths and prompted the introduction of the Food, Drug, and Cosmetic Act in 1938 by the FDA.
• The FDA then introduced safety and efficacy testing
• In 1961, birth defects were associated with Thalidomide.
• In 1962, the Kevauver Harris amendment was enacted, requiring drug manufacturers to prove the effectiveness and safety of their drugs.
• In 1983, guidance for Pharmaceutical Manufacturers and Distributors, known as the Orange Guide, was issued by the MHRA (UK).
• In 1987, the FDA published its validation guideline.
• In 1993, the Barr ruling introduced the concept of three validation batches and representative content uniformity sampling.
• In 2002, the FDA published Pharma GMPs for the 21st Century: A risk-based approach.
• In 2004, the FDA published Guidance for Industry PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance.

Regulatory Changes from 2005-2015

• In 2005, the International Conference for Harmonisation (ICH) published ICH Q9 Quality Risk Management.
• In 2008, ICH published ICH Q10 Quality Systems.
• In 2009, ICH published Q8 Pharmaceutical Development, supporting the use of Quality by Design and Process Analytical Technology (PAT).
• In 2011, the FDA published Process Validation: "General principles and Practices."
• In Oct 2015, Annex 15 Qualification and Validation for the EU was updated, outlining the approach to process validation for Europe.

Regulations & Regulatory Bodies (Part 2)

• Regulatory authorities protect public health and safety within specific regions by granting licenses to companies for medicine manufacturing, distribution, and marketing
• Authorities also monitor medicines, medical devices, and health products
• Authorities create safety and quality information, inspect research and manufacturing companies, and publish guidance documents to ensure compliance.
• The FDA approves medicinal products supplied into the U.S.
• In Ireland, H.P.R.A. is responsible, in the UK it's the MHRA, in the E.U. it's the European Medicines Agency.

Module 2: GMP & Pharmaceutical Quality Systems

Introduction

• Module 2 reviews Good Manufacturing Practice (GMP), the Pharmaceutical Quality System, and their functions.

What is GMP?

• Good Manufacturing Practice (GMP) comprises principles and procedures ensuring product quality.
• GMP is part of quality assurance, ensuring consistent manufacturing and control to appropriate quality standards.

GMP Summary

• GMP ensures products are well-developed, defined, safe, effective, and traceable from start to finish.
• Production and supporting processes need clear definition and documentation in site procedures.
• Equipment, utilities, and facilities must produce products in compliance with specification and without risk of contamination.
• An appropriate level of training for all personnel is necessary

Poor GMP

• Poor GMP can result in customer complaints, product recalls, negative impacts on company image, litigation costs, rejection of batches, investigations, loss of license, and job losses.

Quality Systems

• Quality Systems aim to achieve product realization.
• Quality Systems implement and maintain a system allowing for the delivery of products with the required quality attributes.
• Quality Systems establish and maintain a state of control by developing and using effective monitoring and control systems.
• Quality Risk Management identifies monitors and control systems.

Facilitate Continual Improvement

• Continual Improvement identifies and implements suitable product quality improvements, process improvements, variability reduction, innovations, and PQS enhancements.

Quality Manual

• A Quality Manual describes the Pharmaceutical Quality System (PQS) and includes the Quality Policy.
• The Quality Manual identifies individual Quality System elements, relationships, and Management Responsibility.
• The Quality Policy should comply with regulatory requirements and facilitate continual improvement of the pharmaceutical Quality System.

Quality Manual – Management Responsibilities

• Management should participate in all aspects of the operation of the quality system and take ownership of communication and escalation processes. Management must commit adequate resources to execute the quality system.

Module 3: QSEs Part 1

Introduction

• A Quality System Element is a business process that forms part of the Pharmaceutical Quality System.

Quality Assurance

• Quality Assurance (QA) is part of the Quality Organisation.
• QA ensures compliance with GMP across all process aspects, from starting materials through distribution
• QA makes sure that the products, production and control operations comply with GMP.
• QA ensures that correct supply, in-process tests and controls are carried out and that all items and processes are validated.
• QA finished products are correctly processed and checked per written procedures and not released without certification by a Qualified Person.
• QA monitors product storage, distribution and self-inspection while maintaining the Pharmaceutical Quality System.

Premises & Equipment Areas

• The main areas in a pharmaceutical or bio-pharma plant are production, QC laboratory, warehouse, rest and refreshment, office, and administration.
• The regulations specify the design of GMP facilities, complying with the Code of Federal Regulations CFR 211.42 - 211.72.
• The environment should minimize contamination risks.
• The premises should be carefully maintained and cleaned to not cause hazards to product quality.

Premises and Equipment – Production Area

• All walls, floors, and ceilings should be designed for effective cleaning and disinfection.
• Weighing should occur in a separate room with specific precautions to prevent cross-contamination or cleaning issues.
• Use dedicated and self-contained facilities for highly sensitizing materials or biological preparations.
• Prohibit technical poisons like herbicides and pesticides in premises used for medicinal products.
• Design packaging areas to avoid mix-ups and cross-contamination, with well-lit production areas.

Premises and Equipment – Storage Areas

• Storage areas should be sufficiently sized and designed for their purpose.
• Rejected and returned items should be stored separately.
• Quarantine is ensured via clearly marked separate areas.
• Store highly active materials or products in safe and secure areas.
• Printed packaging materials must be stored safely in order to maintain conformity of the medicinal products

Premises and Equipment – QC Areas

• QC Laboratories should be separate from production for protection.
• Labs handling biological or radioactive samples need special requirements.

Premises and Equipment – Equipment

• Manufacturing equipment should suit its intended purpose, properly designed, located, and maintained.
• Repair and maintenance should not affect product quality and equipment easily cleaned with written procedures and stored only when clean and dry.
• Cleaning and washing should not cause contamination; water pipes carrying purified water should be sanitized per written procedures.
• Calibrated measuring equipment and suitable balances should be available.
• Defective equipment should be labeled and removed.

Calibration

• Calibration ensures instruments or devices produce results within specified limits compared to a traceable standard.
• Accurate measuring devices used in production, control, monitoring processes, and lab testing support batch release, and are calibrated at defined intervals
• Calibrations conform to the manufacturer's accuracy specifications or application tolerances.
• National traceable authorities must oversee Measurement standards.

Instrument Criticality

• A criticality assessment is performed on new instruments to assess their criticality to the product and patients.
• GMP decisions are made on instruments if they perform a GMP function when deciding to release a batch.

Instrument List

• An instrument list includes criticality, calibration details, frequency, and tolerances on a system.
• The calibration program manages activities, ensuring completion within timelines, managed standards, root cause investigations for failures, and maintained procedures.

Technology Transfer

• Technology transfer can be defined as a systematic procedure followed to pass documented knowledge and experience gained during development and commercialization to an appropriate, responsible, and authorized party.
• Tech transfer drivers include scaling up manufacturing, transferring knowledge, and consolidating production due to mergers to maintain supply, volumes & capacity.

The Goals of Tech Transfer

• Product manufactured at the receiving site should match the sending site product in quality
• Regulatory requirements must be satisfied with product specifications
• Transfer deadlines and budgets should be achieved.
• Project initiation comes with the decision to move production across plants

Scope of Transfer

• The scope of transfer covers production process, analytical testing, stability testing, , facility changes, and equipment introduction.

The Two Parties of a Tech Transfer – The Sending Team

• The sending team, the site/development group, currently works on the product.
• The sending team has the knowledge and documentation associated with the product being up to speed with SOPs, BMRs, specifications, regulatory filings like APRs, investigations, and test methods.
• Tacit knowledge is written down and sometimes personnel from the sending site provide on-site training at the receiving site.

The Two Parties of a Tech Transfer – The Receiving Team

• The technology transfer plan is key because it documents the approach, milestones, and deliverables.
• Progress is reported to senior management regularly.

Training

• Training makes sure that employees know how to perform tasks or functions.
• Employees should be given an overview of GMP and GMP standards.
• GMP training is refreshed at intervals with job specific training, including SOPs and safety training.
• Regulator requires Staff training.
• All training needs to be documented with content, assessment and record.
• Curricula covers: SOPs, classroom, and on-the-job training.
• Changes to procedures will be prompted to be read before training effective.
• Visitors or untrained personnel create hazard.
• Full briefing and protective clothing with instructions are necessary.

Module 4: QSES Part 2

Introduction

• Module 4 will look at Quality System Elements in relation to: documentation, supplier qualification and QC testing and stability.

Documentation

• Documentation is a huge part of the Pharmaceutical Industry.
• Specifications for materials, methods, responsibilities, authorities, audit trails are necessary functions of documentation
• The Quality Manual includes the policy and scope of the Pharmaceutical Quality System.
• Other docs identify Quality System elements, their links, interdependencies and management resposibilities.
• Documentation differS from the SOPs and Procedures as this documentation is more prescriptive.

Requirements for Good Documentation

• Documentation requires unique numbers, dated authorization, and approval and must be completed as process proceeds
• Each document must have a record of distribution and be archived when no longer required
• Only ever use current revisions.

Legal Requirements for Documentation

• Documents such as GMP documents needs to stay in retention for 1 year post expiry
• Manufacturers must have access to relevant documentation to solve market issues.
• Integrity must be monitored for duration.
• Documentation is a job within itself

cGMP Documentation

• GMP documents must be accurate and concise and electronic doc management systems must be backed up and validated

Common GMP documents

• The procedures are for uniformity
• Dispense report records materials and quantities dispensed per batch
• BMR = Instructional document & Record
• Specs controlled and required for starting materials
• Analytical report, is for all activity associated with a test
• Cert of analysis = records release testing results
• Records doc calibrations
• Finally validation protocols

Batch Manufacturing Record (BMR)

• A BMR should contain names, batch #, quantity
• Needs personal identifiers
• In process controls, results, equipment.
• Percentage yeild

Standard Operating Procedure

• SOP IS Instructions
• Avoid confusion and general discussions
• All specific information in BMR for processing in detail
• The lab with its methods give detail for testing

Animation Required

• When writing documents if you need to edit,
• Cross it out, initial, date, give a reason for change, don't overwrite

Supplier qualification

• Effectively managing suppliers is a key part of the quality system

Supplier qualification covers the following

• Audits, due dilligence of quality, security, supply chain

QC testing and stability

• QC = part of department with test products + efficany
• Lab testing = material, chemistry, raw etc

QC should over the following

• Samnpling testing specs calib etc
• Documented procedures

QC Lab

• Will perform labs, will conduct tests and give details

Module 5

Validation

• Validation provides a high degree assurance that procedures and equipment meets standards

Qualification

• Qualification relates to quality

• The company will set policies to validate, this will be planned, there will need documentation for findings

EQ

• Each piece of process equipment which can impact quality must be made

1 EQ and report Equipment must have requirements for design Preventtive, clean

Operational Qualification

• Requirements and standards

Pq

• A BILITY TO PREFORM OVER LONG PERIODS OF TIME

Process V

• FDA states data.
• Data Design

3 types of validation procedures

• Design design
• Process qual
• Continued product variation

Cleaning process

• Cleaning to remove the unwanted

Validation

• The study from basis
• Description
• Number to be cleans

5 ms

• Machine
• MEthod
• Materiel
• Measurement
• MEdioum

Cappa

• Documentations
• Causes
• Investigation

MODULE 6

6.02: Audits

• They highlight reasons, they assess performance

Main step

• Plann
• Execute
• Generate Report
• Follow up

Plann

• Decide scope to any issue
• Teams conduct preparation
• Escorts and advice
• Reviews etc

Execution

• Area
• TOurs Docuemntaion

Follow through

• Root casue
• CAPPA

Customers

• Respond, document root cause