Session’s Outline - f-mri.org · Session’s Outline Quality Systems and GMP in Pharmaceutical manufacturing FMRI - Education Program - LU - Jan 31, 2015 1 1. Bio-equivalence 2

Session’s Outline

Quality Systems and GMP in Pharmaceutical manufacturing

FMRI - Education Program - LU - Jan 31, 2015 1

1. Bio-equivalence

2. A 30-minute DVD on GMP

Break

3. Quality Systems and GMPs in Pharmaceutical Manufacturing

4. Good Distribution Practices

5. Questionnaire (could not go through due to time limitation)

Quality Systems and

GMPin Pharmaceutical

Manufacturing

Marleine Akl – Quality Assurance – Algorithm SAL



Introduction & Definition

3 subjects go hand in hand with the basic concept

of Quality:

- Quality Assurance

- Quality Control and

- Good manufacturing Practices

QUALITY has its Origin in a Latin word “Qualitas”

= “General Excellence” or “Distinctive feature”



Introduction & Definition

Quality most simple definition remains

“Fitness for Use or for the Intended Purpose”

ie the patient/user is at focus



Main Goal and Intent

of a Quality System

•Ensuring consistent production of safe and effective

products

•Ensuring full compliance with cGMP regulations

•Providing the framework for achieving stated

requirements thru Quality by Design, Continuous

Improvement and Risk management

•Is based on the fact that Quality is Built in & NOT Tested in

•Is the responsibility of management and requires staff

commitment



Characteristics of a

Successful Quality System

• Science-Based

• Responsive deviation and investigation systems

• Sound method for assessing risk

• Decisions based on an understanding of the intended use of a

product

• Well-defined processes, starting from development and extending

throughout the product life cycle



Current Good Manufacturing Practices



• Serie of principles governing every aspect of producing a drug

• It is that part of QA aimed at ensuring that products are consistently

manufactured to a quality appropriate to their intended use

Global GMP/Quality System

Consists of the following core GMP systems, each covering a specific aspect of the

manufacturing process with many interactions between each of the systems:

•Premises: Facilities and Utilities

•Equipment

•Materials

•Production Operations

•Packaging & labeling

•Laboratory

•Quality

The Quality system provides the foundation for the other systems linking them together.



How do GMPs of different Countries

compare?

At a high level, GMPs of various regulatory authorities •US 21 CFR Parts 210/211

•EU Eudralex volume 4 – Directive 2003/94/EC

•WHO cGMP

•International Conference on Harmonization (ICH)

•Lebanon GMP - Issue of 2009 (Decision 212/1)

have practically the same global requirements:

➢ Equipment & facilities being properly

designed, maintained, & cleaned

➢ SOPs be written & approved

➢ An independent Quality unit

➢ Well trained personnel & management



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Lifecycle follows below model:

• Applies to all GMP areas

including the laboratory

equipment

• Design and test results need approval prior to start of use

• Steps 1 5 (Qualification phase) need to be completed prior to start of cleaning and process validations ie prior to use for product manufacturing

GMP Facilities, Utilities, & Equipment

Lifecycle

1. Assess

Need &

Impact 2. Define

requirements 3. Design 4. Design

Review 5. Test &

Release

(IQ/OQ/PQ) 6. Operate

7. Maintain

8. Retire


FMRI - Education Program - LU - Jan 31, 2015

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Any building used in the manufacture, processing, packing, or holding of a

drug product shall be:

• Of suitable size, construction, and location to facilitate cleaning,

maintenance, and proper operation.”

• Designed in line with the intended manufacturing operations and

type of products (solid dosage forms, liquid forms, sterile forms etc…)

• Facilities for highly sensitizing or toxic products shall be

completely separate from those for other drug products for

human use.

PREMISES

Facilities



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Design should ensure:

a. Prevention of contamination from surrounding environment and pests

b. Prevention of mix up of materials and products

c. Ancillary areas such as change rooms, Laundry, Rest and refreshment rooms should be

separated from production & QC laboratory areas, and should be easily accessible &

appropriate for the number of users.

d. Quality Control Laboratories should be designed to suit the operations to be carried out

in them, be separate from production areas, and areas where biological, Microbiological

or radioisotope test methods are employed should also be separate from each other.

e. Defined areas for certain activities (e.g material sampling & dispensing)

f. Storage areas of adequate space

g. Finishing: Wall, ceiling, drains, lighting, pipe work and light fitting, sewage and refuse

PREMISES

Facilities



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WEIGHING & SAMPLING AREAS:

• Should be separate

• Specially designed for that use and operated to prevent cross-contamination and mix-ups.

STORAGE AREAS of materials/ products should ensure adequate:

a. Space, design, security and cleanliness

b. Storage of quarantine stocks, Rejects, Recalled or Returned products

c. Storage of hazardous substances and controlled substances

d. Environmental conditions of storage area (e.g. T°C & RH)

e. Receiving of incoming materials

PREMISES

Defined Areas for Certain Activities



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ALL FACILITY COMPONENTS NEED TO:

COMPLEMENT EACH OTHER TO ENSURE A LOGICAL FLOW OF MATERIALS AND

PERSONNEL

i.e Product Areas should preferably be laid out in such a way to:

• Allow production to take place in areas connected in a logical order corresponding

to the sequence of the operations and the required cleanliness levels

• Avoid crowding and disorder,

• Allow effective communication and supervision.

PREMISES

Facilities



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Qualified Utilities and Equipment mainly consisting of:

• Power Supply System

• Water Treatment System:

Ensuring the required Quality of Water to be used in the manufacture of the product and complying with

current compendia eg USP, EP… and for the intended purpose.

• Air Handling and Treatment System:

Ventilation, Air Filtration, Air Heating and Cooling for adequate control of air balancing, dust, humidity, and

temperature throughout the manufacture, processing, packing, or holding of a drug product.

• Compressed Air System

• Steam

• All necessary Equipment to operate in Production, QCL, warehouses etc…

• Computer Systems (as applicable)

• Good compliant periodic Calibration and Maintenance program

• Adequate Personnel Dress Code & Access Control

PREMISES

UTILITIES



Materials Quality System (Raw materials, Packaging Components and Finished products)

Four Key elements:

• Materials management: all activities, for materials and product, related to receipt, storage, status control, warehouse practices (wooden vs plastic

pallets, physical segragation, controlled storage conditions etc…) and inventory management (FIFO / FEFO)

• Distribution of the Finished product: Preparation of Orders, Picking/Packing, Transport monitoring (Environmental conditions - T°C/RH, safe adequately labeled containers), Traceability, Documentation and Reconciliation

• Supplier Quality Management (Supplier evaluation/Qualification: Certified vs non-certified etc…)

• GMP Service providers & Consultants (Supplier evaluation)



Production Operations

All Manufacturing operations follow the same pattern ie Dispensing the correct

material for a batch, Compounding then subdividing into unit doses

They accordingly should be designed to ensure:

• Contamination Control (product protection and contamination control to address bioburden, chemical & physical sources of contamination operators

dress code, reusable pallets cleaning & storage, Environmental monitoring, processing highly toxic or sensitizing materials etc…)

• Adequate preparation, Set-up & Processing (line clearances, dispensing operations, in-process

controls, Metal detection for capsules & tablets etc…)

• Post processing activities (yield verifications vs the theoretical expected yield ranges, reconciliation,

equipment cleaning and line closing etc…)

• Re-processing rules

They consequently should be carried out according to the related:

• Master Production records (detailed manufacturing and packaging instructions, including safety,

environmental and contamination control instructions, and complying with marketing authorization)

• Batch production records (must be issued from the approved master record with unique identification etc…)



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Packaging & Labeling

• Packaging materials: • Must conform to established specifications and regulatory requirements

• Suitability of the primary packaging for the product must be supported by data

• Access to pre-printed packaging material should be limited to authorized personnel

• Quantities of printed materials must be reconciled

• Packaging operations: • Lot number and expiration date are mandatory on primary and secondary packaging (date format

MM/YYYY)

• Encoding is critical (datamatrix, track and trace system)

• 100% verification of printed materials identity on line

• 100% verification of encoding on line

• 100% verification of market pack integrity on line



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Laboratory Quality System

• Management and handling of Samples: safeguard at all times the identity and

integrity of samples storage, security, safety etc…

• Management of reference standards and reagents: safeguard at all times

identity and integrity of standards/reagents/media/solutions, validity, security and safety

• Testing: Glassware handling, Methods used, Equipment used cleaning, validation, Qualification, periodic

calibration, etc…

• Documentation: safeguard at all times the identity and integrity of all data Reporting, Recording,

verifications, compliance with cGLP/cGLP, retention, security, safety (archiving system), etc…

• Data Review, Analysis and Evaluation: Comprehensive review, interpretation and

assessment by a qualified person

• Investigation of Suspect Results: first in the lab than extending if need be to

manufacturing; practically same elements as deviations with requirements for allowing re-sampling/retest, specific points

for investigations in microbiology, etc…



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Quality System

The Quality system provides the foundation for the other systems linking them together.

It contains the key elements of:

•Quality Management

•cGMP Expectations for:

•Documentation

•Personnel qualification

•Deviation

•Change Management

•Auditing & Self-assessment

•Product Quality Assurance and

•Patient safety assurance



Quality Management

Personnel Responsibilities



Quality Systems

Responsibilities

& Governance

Delegation

Management Responsibilities

Quality Unit

Risk Management

Standards, Procedures &

Quality manual

Sustaining & Improving

Quality Systems

Management Reviews of

Quality Systems

Monitoring & Evaluation

Preventive & Corrective

actions

Quality Plans

Quality Systems

Definition

Product Quality Assessment

Quality Unit Responsibility in Brief

INDEPENDENT OF PRODUCTION

FULFIL QUALITY ASSURANCE AND QUALITY CONTROL RESPONSIBILITIES; MAYBE

COMBINED OR SEPARATE

RESPONSIBLE FOR ENSURING ALL PRODUCTS AND MATERIALS MEET REQUIREMENTS

FOR INTENDED USE

GMP DECISIONS ARE FINAL AND CAN NOT BE OVERRULED BY OTHER FUNCTIONS

MUST APPROVE ALL APPROPRIATE QUALITY RELATED DOCUMENTS

MUST BE INVOLVED IN ALL QUALITY RELATED MATTERS

HAVE THE AUTHORITY TO ACCESS AREAS AND RECORDS NECESSARY TO EXECUTE

THEIR RESPONSIBILITY

HAVE THE AUTHORITY TO HALT PRODUCTION AND PLACE PRODUCTS ON HOLD OR

QUARANTINE STATUS TO ENSURE RESOLUTION OF QUALITY ISSUES



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Documentation Fundamental Principle: every action will only be undertaken by following approved written procedures

Design



ALL TYPES of

DOCS:

•Procedures

•Instructions

•Plans

•Reports

•Records

•Title

•Document

code

•Version &

Page

numbering

•Reason for

revision

•Purpose

•Authors &

Approvers

Prepare

Described

by SOP

Review Approve Distribute

Arc

hiv

e

Destro

y

Maintenance

•Content verification

•Signed/dated by authors

•Accurate description of activity

performed

•Acceptance criteria

•Approval by area supervision,

technical services & Quality

PRIOR to Execution

•Only

current

versions

available for

user

•Periodic review (routinely 2-3 years)

•Safeguard history of Doc.

•Ensure no use of superseded docs

•Specified Retention Period

•Legibility of Doc. thru retention

• At the end of the specified

Retention Period

•Document destruction

•Other Practices to be

ensured eg: 2nd person

verification, proper and

timely recordings, proper

corrections, entries in

chronological order, date

format, etc…

•Data Integrity and

Traceability to be

safeguarded/maintained

at all times

Personnel Qualification

•Personnel must be qualified PRIOR to performing assigned tasks/duties •Qualification is achieved based on:

– Education – Experience and –Training of the individual

•Qualification program to be based on cGMP regulations and appropriate standards related to the job requirements •The Quality Unit and appropriate area supervision must approve the qualification requirements and the training material •Trainers Must be Qualified •Training Records should be retained for each employee •Training appropriateness and effectiveness to be re-assessed periodically and, if needed, corrective action taken •Continuous Training is critical



Deviations’ Handling

Identify

& Report



•All personnel

are responsible

for identifying

and reporting to supervision

•Should be noted

immediately on relevant GMP doc.

Notify the Quality Unit

•As soon as

identified (within 1

working day)

•In written

Investigate

& Document

Corrective & Preventive

Actions (CAPA)

Trend

Analysis

•Assess & Assign Criticality of deviation

•Assess Impact on other batches, materials and

processing systems Risk Evaluation

•Investigate the 5Ms Identify Root cause (s) Corrective action(s)

•Complete report within a specified timeframe

•Report to be Approved by area supervision and Quality

•Develop CAPA plan

•Follow-up on its implementation/dates

•Trend and Track all deviations CAPA

Evaluate effectiveness of actions

Change Management

•Changes can be triggered by new standards, Regulatory and or Business requirements,

suppliers’ limitations, or need for improvement (procedural, equipment, facility etc…)

•A Change management system must be in place to ensure:

• Changes that could affect the quality of a product or reproducibility of the process

are comprehensively planned, fully Identified, Assessed, Documented,

Approved, Implemented and Evaluated for Effectiveness

• Risk management is applied through classification of changes, impact

analysis (internal, external) and subsequent levels of control

• Changes are tracked

• After implementation, an appropriate number of batches are evaluated according

to acceptance criteria to ensure change effectiveness and no unintended

consequences



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Auditing (Self-Assessment / Self-Inspection)

Audit Program (type/scope of audit, frequency etc…)

Audit Plan (Agenda, auditors, dates, etc…)

Audit Preparation (notify party to be audited, logistics etc…)

Audit Execution

Audit Report

Tracking Actions

Audit System Self-Assessment

Due Diligence

Cause Audits

Trend Analysis

Documenting & Tracking

Observations Report & Categories

Audit Response

Final report



Product Quality Assurance &

Patient Safety Assurance

•Specifications (including expiration dating)

•Validation & Qualification Practices (IQ, OQ, PQ need to be finalized and

approved before Cleaning and Process validation can start)

•Batch Disposition (Release)

•Periodic product and systems reviews

•Stability Testing

•Complaints & Recalls



Thank You



Good Distribution Practices

GDP

Marleine Akl – Quality Assurance – Algorithm SAL

GDP – FMRI

Education Program - LU - Jan 31, 2015

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OUTLINE

• Distribution in Pharmaceuticals • Why has GDP become such a hot topic? • What has been the Response? • Key Elements of Regulations • Revised GDP Guidelines

GDP - FMRI - Education Program

LU - Jan 31, 2015

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Distribution in Pharmaceuticals Aims at

▫ Delivery to pharmacies without alteration of product properties

▫ A Quality System that would ensure:

Authorised persons/institutions

Storage conditions observed (including transport)

No contamination or product adulteration

Stock turnover

Stored safe and secure

Right product, right address, satisfactory time period

Tracing system to allow recall


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WHY HAS GDP BECOME SUCH A HOT TOPIC?

Distribution / Supply Chain 1970's: Prevailing simple linear business model, Local market management and predominantely small molecule manufactured by chemical synthesis. 1980‟s: Outsource non-core activities Manufacture, analytics, distribution, storage

Storage & Transportation

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DIS-Integration of the Supply Chain


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Integrity Issues • Economically motivated adulteration

“Heparin, supplied by Baxter, found to be

adulterated, with reports of 574 adverse events

and nine patient deaths estimated

• Recalls associated with supply chain

issues (J&J/McNeil)

• Loss of hundreds of millions $ in

manufacturing issues (Novartis)

• Shortages in US/EU supply chains

result in governments and general

public questions

Security Issues • “Abbott was hit by $4m diagnostics

theft in USA” (June 2011)

• “Eli Lilly warehouse thieves make off with $76m haul” (March 2011)

• Counterfeiting – “Operation Singapore, 2 million doses of counterfeit medicine enter UK supply chain in 2006/7”.

• Persistent concerns that the drug supply is increasingly vulnerable to diversion of legitimate drugs (ie stolen or sold illegally)

GDP - FMRI - Education Program -

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• Crippling impacts on

▫ Patient safety

▫ Brand image and reputation

▫ Costs of remediation

▫ Customer service and confidence.

A UNIVERSAL CRY FOR CHANGE!


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What Has Been The Response? Regulators collaborating globally - EU, US, PIC/S...

• Dramatic tightening of GDP/GMP • EU implemented Falsified Medicines Directive (2011/62/EU).

• EU Revised Guidance on Wholesale Distribution Practice (2013/C 68/01)

• WHO Revised good distribution practices for pharmaceutical products (WHO technical report series, No. 957, 2010)– Annex 5 – 2011

• For US:

▫ USP Chapters regarded as FDA benchmark were revised:

Chapter<1079> “Good Storage & Distribution Practices for Drug Products”

Chapter <1083> “Good Distribution Practices-Supply Chain Integrity” ▫ FDA joined the Pharmaceutical Inspection Co-operation Scheme (PIC/S). ▫ FDAs “Pathway to Global Safety and Quality” for systems to collect and share data

between competent authorities across the world. • GS1 Global Traceability Standard for Healthcare (GTSH). • Track & Trace Serialization implementation

• Guidelines on Good Storage and Distribution Practices of Pharmaceutical Products in Lebanon - Edition 2 – 2014


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Key Elements in Regulations

• Responsible person (oversees Quality System)

• Written contracts with Suppliers and Representatives

• Written procedures

• Checking Bona Fides of suppliers and customers

• Staff Training

• Records/traceability

• Counterfeit Medicines


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Directive: Falsified Medicinal Products 2011/62/EU - SCOPE

• Extending regulation to brokers of medicines • Strengthened obligations on wholesale dealers

• Improving controls on quality of active substances and certain excipients • Regulating medicines imported for re-export – new term “introduced” and

rules governing access to medicines held in free trade zones & warehouses • Requiring safety features for medicines at risk of counterfeiting • Addressing the internet supply of medicines • Strengthening inspection and ensuring appropriate penalties for

counterfeiting are in place in Member States


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Revised Guidelines on GDP

• Quality Management ▫ Senior management commitment ▫ Management of outsourced activities ▫ Risk management ▫ Quality System:

Documentation and procedures Traceability of pharmaceutical products Handling Complaints Handling Recalls Handling Returned Goods

• Personnel ▫ Responsible Person ▫ Organisation chart ▫ Training in GDP


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Revised Guidelines on GDP (Cont‟d)

• Premises, warehousing & Storage

▫ Storage areas

▫ Storage conditions

▫ Stock control

• Operations ▫ Shipment containers and container labelling

▫ Dispatch and receipt

▫ Repackaging and relabeling

▫ Qualification of suppliers and customers


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• Suspected falsified medicines ▫ Distributors must inform competent authority and

MAH immediately according to a defined procedure.

• Contract Operations ▫ Written Quality/ Technical agreements allocating

responsibilities Required between all actors in the supply chain with the Marketing

Authorisation Holder (MAH) shouldering more responsibility.


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• Transportation ▫ Delivery drivers identified and trained in GDP

▫ Vehicles equipped with location tracing devices and shipment conditions monitoring devices

▫ Maximum limit of 24 hours for transport hubs

▫ Wholesalers distribution authorisation: More stringent control in storage whereby some actor/logistics providers,

holding product for greater that 24 hours, may require a Wholesale Dealer Licence (WL).

• Specific provisions for Brokers ▫ Register and have quality management system


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GMP Regulations tightening

• Traceability reflected in Chapter 5 of GMP Guidelines: requirement for “A record of where each active substance (including its critical starting materials) is manufactured, propagated, processed and handled prior to its use in the manufacture of a medicinal product”.

• Tightening of requirements to check „Bona Fides‟ of supply sources (qualification of suppliers) and other trading partners.

• Safety features required for products at risk of counterfeiting (eg. serialisation/authentication) Barrier: Complex and expensive technology options


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Questions?

Thank You


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Documents

Session’s Outline - f-mri.org · Session’s Outline Quality Systems and GMP in Pharmaceutical manufacturing FMRI - Education Program - LU - Jan 31, 2015 1 1. Bio-equivalence 2