THE ROLE OF QA IN PHARMACEUTICALS

THE ROLE OF QUALITY ASSURANCE IN PHARMACEUTICALS

History, Current Trends And Future Challenges

National and Kapodistrian University of Athens – Department of Pharmacy

Athens, 20th of May 20161

QUALITY ASSURANCE IN PHARMACEUTICALS

Currently Called

“PHARMACEUTICAL QUALITY SYSTEM”

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HISTORY OF PHARMACEUTICAL QUALITY SYSTEM

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History Of PHARMACEUTICAL GMP

Pharmaceutical regulations and

GMP requirements were created

and put in place as responses to

tragic circumstances and to prevent

future tragedies.

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• 1901 - children who received antitoxin for diphtheria

treatment died of tetanus because the horse serum that had

been used to prepare the antitoxin was contaminated with

tetanus.

• syrup to calm “colicky” babies and “tonics” for adults often

contained alcohol, opium, or morphine, which addicted many

people who used them.

Response: 1906 Pure Food and Drug Act – First Act required

selected dangerous ingredients to be labeled on all drugs.

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• 1930s - The wrong raw material and an elixir of sulfanilamide, anti-infective drug used in 1935. One company used diethylene

glycol, a poisonous solvent and chemical analog of antifreeze, in

an oral “elixir of sulfanilamide.” Before the problem was

discovered, 107 people died, many of them children.

Response: Congress passed the Federal Food, Drug and Cosmetic

(FD&C) Act of 1938. For the first time, companies were required to

prove that their products were safe before marketing them. Still this

major act covering till today FDA oversight to cosmetics and

therapeutic devices.

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• In 1941, nearly 300 people were harmed (some of them died)

by one company’s sulfathiazole tablets, a sulfa drug tainted

with the sedative phenobarbital.

Response: That incident caused FDA to drastically revise

manufacturing and quality control requirements, leading to what

would later be called GMPs.

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SULFATHIAZOLE TABLETS

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• 1960s - Thalidomide was marketed in Europe as a sleeping pill

and to treat morning sickness. When regulatory agencies gave

permission to sell the drug for that indication, they had no

knowledge of its serious side effects. It turned out to be

teratogenic: It caused serious deformities in developing

fetuses.

Response: Manufacturers must prove efficacy of products before

marketing them and ensure stricter control over drug testing.

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THALIDOMIDE TRAGEDY

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Children whose mothers

took thalidomide in the first

trimester were born with

severely deformed arms and

legs. An estimated 10,000

cases of infant deformities in

Europe were linked to

thalidomide use.


• 1970s - The 1972 Devonport, UK, incident resulted in at least five deaths when drug products designed to be sterile became contaminated and recipients developed infections. An unwritten change to autoclave operation, communicated orally between operators, resulted in dextrose IV solutions that were not uniformly sterile.

Response: GMPs for drugs (21 CFR Parts 210 and 211) and medical devices (21 CFR 820) were made final in 1978. They were intended to help ensure the safety and efficacy of all products.

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• 1980s - Poisoned acetaminophen capsules. In 1982, 12-year-old Mary Kellerman died after taking an extra-strength Tylenol acetaminophen capsule, Six other people died after taking the same drug. Johnson & Johnson announced a nationwide recall of 31 million bottles of Tylenol. The investigation revealed that a criminal tamperer had opened up and laced some capsules with cyanide. The company destroyed all 31 million bottles of the largest-selling over-the counter (OTC) medicine in the country.

Response: FDA issued tamper-resistant packaging regulations for all OTC human drug products and incorporated them into the GMPs. Congress passed the Federal Anti-Tampering Act in 1983, making it a crime to tamper with packaged consumer products.

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ACETAMINOPHEN CAPSULES

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• In the 1980s, FDA began publishing a series of guidance

documents that have had a major effect on our interpretation of

current GMPs.

• Issuance of Guideline on General Principles of Process Validation

in 1987 outlined current thinking or expectations of process

validation for drugs and devices.

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• In 1989, an outbreak of toxic reactions to over-the-counter l-

tryptophan, a dietary supplement, resulted in 38 deaths and

probably thousands of less severe reactions. The event was the

result of a manufacturing process change that increased the

level of a harmful byproduct. Doses that had previously been

safe now caused toxicity.

Response: clarification of requirements for characterizing drug

impurities and new requirements for evaluation of minor

impurities.

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BASIC MILESTONES IN HISTORY OF PHARMACEUTICAL REGULATIONS

AND GMP• 1906 Pure Food and Drug Act

• 1938 Federal Food, Drug and Cosmetic (FD & C) Act

• 1941 Tragedy with Sulfathiazole tablets tainted with Phenobarbital

Result: FDA revises manufacturing and quality controls drastically,

the beginning of what will later be called GMPs.

• 1962 The “Thalidomide Tragedy” leads the US Congress to add

GMP to the Food, Drugs and Cosmetic Act. FDA publishes first

Regulation on Good Manufacturing Practices” – A drug which is

not made following GMP is adulterated (Contaminated).

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AND GMP• 1969 The World Health Organization publishes the first

universal guideline “Basic Rules for the Manufacture of

Pharmaceuticals and the Assurance of their Quality”.

• 1974 Allergic reaction due to extremely small traces of

penicillin in other drug products lead to demands for

separation of penicillin and non-penicillin production.

• 1975 The EU Directive 75/319 lays down the basic procedures

(approximations) for the registration, trade and compensation

for damages for “Medicinal Products” with the EU.

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AND GMP• 1978 CGMPs Final Rules for Drugs (21 CFR Parts 210–211).

• 1982 Temper-Resistant Packaging Regulations Issued for OTC

Products.

• 1987 Guideline on General Principles of Process Validation.

• 1989 EU publishes its Directive on the “Approximation of

provisions for GMP in the European Community”, i.e. a legal

basis is established for pharmaceutical GMP within the

European Community.

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AND GMP• 1996 PIC accepts the European industry’s GMP Guide.

• 1998 “GMPs for Starting Materials” is added to the ICH work programme to be decided by an Expert Working Group.

• 2001 ICH Q7A API Guidance ICH’s “Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (APIs)”.

• 2001 – Issuance of Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use.

• 2011 – Issuance of Directive 2011/62/EU of the European Parliament and of the Council for prevention of the entry into the legal supply chain of falsified medicinal products.

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PRESENT – PRINCIPLES OF PHARMACEUTICAL QUALITY

SYSTEM

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WHAT IS QUALITY ?

• Quality is not an act, is a habit (Aristotle)

• Quality means: Do it right when no one is looking (Henry Ford)

• Fitness for Use (Juran)

• Conformity with Specifications (Crosby)

• Capability of product to satisfy customer’s needs (Ishikawa)

• Quality is inversely proportional to variability (Montgomery)

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WHAT IS QUALITY OF DRUG ?

• The degree to which a set of inherent properties of a product,

system or process fulfills requirements specifically for quality

of drug substance and drug product (ICH Q9).

• The suitability of either a drug substance or drug product for

its intended use. This term includes such attributes as identity,

strength and purity (ICH Q6A).

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WHAT IS GMP(GOOD MANUFACTURING

PRACTICE) ?• The part of quality assurance which ensures that products are

consistently produced and controlled in accordance with the

quality standards appropriate to their intended use and are in

compliance with their marketing authorization specifications

(Directive 2003/94/EC).

• GMP involves also Production and Quality Control of

Pharmaceutical products.

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WHAT IS QUALITY CONTROL (QC) ?

Quality control is that part of Good Manufacturing Practice

(GMP) which is concerned with sampling, specifications and

testing and with the organization, documentation and release

procedures which ensure that the necessary and relevant tests

are actually carried out and that materials are not released for

use, nor products released for sale or supply, until their quality

has been judged to be satisfactory (EU GMP Part I).

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WHAT IS QUALITY ASSURANCE (QA) IN PHARMACEUTICALS ?

Quality assurance (or Quality Management) is a wide-range

concept covering all matters that individually or collectively

influence the quality of a product. It is the totality of the

arrangements made with the object of ensuring that

pharmaceutical products are of the quality required for their

intended use (WHO). Quality Management therefore

incorporates Good Manufacturing Practice.

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WHAT IS PHARMACEUTICAL QUALITY (MANAGEMENT) SYSTEM

PQS ?

Management system to direct

and control a pharmaceutical

company with regard to quality.

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PHARMACEUTICAL QUALITY SYSTEM (PQS)

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QC

GMP

QA

PQS SHOULD ENSURE

• Manufacture of medicinal products with appropriate quality

attributes.

• Product and process knowledge is managed throughout all

lifecycle stages; Pharmaceutical Development Technology

Transfer Commercial manufacturing Product

Discontinuation

• Good Manufacturing Practice is always taken into

consideration through design, development and manufacture

of products with clearly specified manufacture and control

operations.28

PQS SHOULD ENSURE

• Managerial responsibilities are clearly specified.

• Supply and use of the correct starting and packaging

materials, from the approved suppliers and supply chain.

• Processes are in place to assure the management of

outsourced activities.

• A state of control is established and maintained by developing

and using effective monitoring and control systems for process

performance and product quality.

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PQS SHOULD ENSURE

• Deviations during manufacture or control should be

investigated, Root Cause should be found and appropriate

CAPAs should be undertaken in order to avoid potential

deviations occurring in the future. Effectiveness of CAPAs

implementation should be evaluated through Quality Risk

Management principles (QRM).

• All necessary controls on intermediate products, and any other

in-process controls and validations are carried out.

• Continual improvement of PQS is facilitated through the

implementation of quality improvements through gained

knowledge from process and product (QbD, SPC, PQR).30

PQS SHOULD ENSURE

• Evaluation of planned changes and their approval prior to

implementation, taking into account regulatory notification and

approval where required through Change Control

management.

• Evaluation of changes to confirm the quality objectives were

achieved and that there was no unintended deleterious impact

on product quality.

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PQS SHOULD ENSURE

• Medicinal products are not sold or supplied before batch

release certification by Qualified Person (QP).

• Medicinal products are stored, distributed and subsequently

handled so that quality is maintained throughout their shelf life

(GDP).

• Regular self-inspection and/or quality audit for appraisal the

effectiveness and applicability of the Pharmaceutical Quality

System.

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BASIC ELEMENTS OF PQS

• Senior management has the ultimate responsibility to ensure

an effective Pharmaceutical Quality System is in place,

adequately resourced and that roles, responsibilities, and

authorities are defined, communicated and implemented

throughout the organisation.

• Management review, with the involvement of senior

management, of the operation of the Pharmaceutical Quality

System to identify opportunities for continual improvement of

products, processes and the system itself.

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BASIC ELEMENTS OF PQS

The Pharmaceutical Quality System

should be defined and documented.

A Quality Manual or equivalent

documentation should be

established and should contain a

description of the quality

management system including

management responsibilities.

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EU GMP CHAPTERS

• Chapter 1 – Pharmaceutical Quality System

• Chapter 2 – Personnel

• Chapter 3 – Premises and Equipment

• Chapter 4 – Documentation

• Chapter 5 – Production

• Chapter 6 – Quality control

• Chapter 7 – Outsourced activities

• Chapter 8 – Complaints, quality defects and product recalls

• Chapter 9 – Self inspection35

CHAPTER 1 - PHARMACEUTICAL QUALITY SYSTEM

• The design of the system should incorporate appropriate risk

management principles including the use of appropriate tools.

• Pharmaceutical Quality System should facilitate innovation and

continual improvement and strengthen the link between

pharmaceutical development and manufacturing activities.

• It should be fully documented and its effectiveness monitored.

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CHAPTER 2 - PERSONNEL

• Personnel should have the necessary qualifications and practical

experience.

• Personnel in responsible positions should have specific duties

recorded in written job descriptions and adequate authority to

carry out their responsibilities.

• Personnel whose duties take them into production and storage

areas or into control laboratories, and for other personnel whose

activities could affect the quality of the product, such as cleaning,

maintenance, validation, etc., should be trained regularly.

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CHAPTER 3 - PREMISES AND EQUIPMENT

• Premises and equipment must be located, designed,

constructed, adapted and maintained to suit the operations to

be carried out. Their layout and design must aim to minimise

the risk of errors and permit effective cleaning and

maintenance in order to avoid cross-contamination, build-up of

dust or dirt and, in general, any adverse effect on the quality of

products.

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CHAPTER 4 - DOCUMENTATION

• The various types of documents, instructions and records used

should be fully defined in the manufacturer's Pharmaceutical

Quality System.

• Good documentation constitutes an essential part of the quality

assurance system and is key to operating in compliance with GMP

requirements.

• Suitable controls should be implemented to ensure the accuracy,

integrity, availability and legibility of documents. Instruction

documents should be free from errors and available in writing.

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CHAPTER 4 - DOCUMENTATIONContinue

Basic types of GMP documents required in PQS:

• Site Master File (SMF)

• Quality Manual

• Quality Policies

• Standard operating procedures (SOPs)

• Specifications

• Manufacturing Formulae, Processing, Packaging and Testing Instructions

• Protocols

• Technical – Quality agreements40

CHAPTER 5 - PRODUCTION

• Production operations must follow clearly defined procedures;

they must comply with the principles of Good Manufacturing

Practice in order to obtain products of the requisite quality and

be in accordance with the relevant manufacturing and

marketing authorisations.

• Prevention of cross-contamination in production.

• Validation: all manufacturing, packaging, testing and other

processes which may have an impact to quality of the drug

product should be validated and fully documented.

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CHAPTER 5 – PRODUCTIONContinue

Starting materials including APIs, excipients, primary

and secondary packaging materials should be

procured by approved and qualified vendors and

their quality should be assessed against pre-defined

quality specifications before their use in

manufacturing and packaging processes.

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CHAPTER 6 – QUALITY CONTROL

• Quality Control is concerned with sampling,

specifications and testing as well as the organisation,

documentation and release procedures which ensure that

the necessary and relevant tests are carried out, and that

materials are not released for use, nor products released

for sale or supply, until their quality has been judged

satisfactory.

• The independence of Quality Control from Production is

considered fundamental to the satisfactory operation of

Quality Control.43

CHAPTER 6 – QUALITY CONTROLContinue

Other duties of Quality Control:

• Establishment, validation and implementation of all quality

control procedures.

• Oversee the control of the reference and/or retention samples

of materials and products.

• Ensure the correct labelling of containers of materials and

products.

• Ensure the monitoring of the stability of the product.

• Participate in the investigation of complaints related to the

quality of the product. 44

CHAPTER 7 – OUTSOURCED ACTIVITIES (Subcontracting)

• Any activity covered by the GMP Guide that is outsourced

should be appropriately defined, agreed and controlled in

order to avoid misunderstandings which could result in a

product or operation of unsatisfactory quality.

• There must be a written Contract between the Contract Giver

and the Contract Acceptor which clearly establishes the duties

of each party.

• The Quality Management System of the Contract Giver must

clearly state the way that the Qualified Person certifying each

batch of product for release exercises his full responsibility.45

CHAPTER 8 – COMPLAINTS, QUALITY DEFECTS AND PRODUCT

RECALLS• A system and appropriate procedures should be in place to

record, assess, investigate and review complaints including

potential quality defects, and if necessary, to effectively and

promptly recall medicinal products from the distribution

network.

• Root cause analysis (RCA) work should be applied during the

investigation of quality defects.

• The effectiveness of recall procedure should be periodically

evaluated to confirm that they remain robust and fit for use

through mock-recalls performance. 46

CHAPTER 9 – SELF INSPECTION

• Self inspections should be conducted in order to monitor the

implementation and compliance of PQS with GMP principles

and to propose necessary corrective measures.

• Self inspections at production, quality control, storage areas,

premises, maintenance, distribution chain, etc. should be

examined at intervals following a pre-arranged programme in

order to verify their conformity with the principles of Quality

Assurance.

• Self inspections should be conducted in an independent and

detailed way by designated competent person(s) from the

company. 47

PHARMACEUTICAL QUALITY SYSTEM – SIX SYSTEMS FDA

APPROACH• Quality System

• Production system

• Facilities and equipment

system

• Materials system

• Laboratory controls system

• Packaging and Labelling

system

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DEVIATION INVESTIGATION AND ROOT CAUSE ANALYSIC (RCA)

• Root cause analysis work should be applied during the

investigation of quality defects.

• In cases where the true root cause(s) of the quality defect

cannot be determined, consideration should be given to

identifying the most likely root cause(s) and to addressing

those.

• Appropriate CAPAs should be identified and taken in

response to a quality defect. The effectiveness of such actions

should be monitored and assessed.

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DEVIATION INVESTIGATION AND ROOT CAUSE ANALYSIS (RCA)

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ROOT CAUSE ANALYSIS –FISHBONE DIAGRAM (ISHIKAWA)

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ROOT CAUSE ANALYSIS – 5 Whys

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ROOT CAUSE ANALYSIS – 5 Whys example in Pharmaceuticals

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ROOT CAUSE ANALYSIS -BRAINSTORMING

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QUALITY RISK MANAGEMENT

• Quality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle.

• Harm – damage to health, including the damage that can occur from loss of product quality or availability.

• Hazard - the potential source of harm.

• Risk – the combination of the probability of occurrence of harm and the severity of that harm.

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QUALITY RISK MANAGEMENT

OVERALL RISK = S x O x D

S = Severity of the consequences of the harm

O = Probability of occurrence of the harm

D = Detectability, ability to detect the hazard

(source of harm)

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QUALITY RISK MANAGEMENT FLOW CHART (ICH Q9)

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PRODUCT QUALITY REVIEW

• Review of starting materials including packaging materials used in the product.

• Review of critical in-process controls and finished product results (SPC, trend analysis).

• Review of all significant deviations or non-conformances, their related investigations, and the effectiveness of resultant corrective and preventive actions taken.

• Review of all changes carried out to the processes or analytical methods.

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PRODUCT QUALITY REVIEWContinue

• Review of Marketing Authorisation variations submitted, granted or refused, including those for third country (export only) dossiers.

• Review of the results of the stability monitoring programme and any adverse trends.

• Review of all quality-related returns, complaints and recalls and the investigations performed at the time.

• Review of adequacy of any other previous product process or equipment corrective actions.

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PRODUCT QUALITY REVIEWContinue

• For new marketing authorisations and variations to marketing

authorisations, a review of post-marketing commitments.

• The qualification status of relevant equipment and utilities, e.g.

HVAC, water, compressed gases, etc.

• Review of any contractual arrangements as defined in Chapter

7 (Technical – Quality agreements) to ensure that they are up to

date.

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STATISTICAL PROCESS CONTROL (SPC) AND TREND ANALYSIS

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OUT OF CONTROL STATE IN CONTROL STATE

STATISTICAL PROCESS CONTROL (SPC) AND TREND ANALYSIS

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CONTINUOUS IMPROVEMENT OF PHARMACEUTICAL QUALITY

SYSTEM – PDCA CYCLE (E. Deming)

Plan: Corrective and

Preventive actions (CAPAs)

Do: implementation of CAPAs

Check: evaluation of

effectiveness of CAPAs

Act: Decision for new CAPAs

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FUTURE OF PHARMACEUTICAL QUALITY SYSTEM

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• Till today pharmaceutical product quality is assured by

pharmacopoeal “end point” testing – after the fact quality

control in finished product (Assay, related substances,

dissolution test in tablets, etc.).

• This end-point quality testing was realized to be insufficient to

assure the quality of the individual medication unit (the tablet,

the capsule, the vial) dispensed to the patient.

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• Quality needed to be assured at each step of the

manufacturing process to be as certain as possible that each

dosage unit met its quality specifications.

• Change from traditional quality-by-testing (QbT) approach to

the new quality-by-design (QbD) approach.

• Implementation of Quality Risk management in all steps of

product lifecycle, from product development to product

discontinuation.

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PROCESS ANALYTICAL TECHNOLOGY (PAT)

Process Analytical Technology (PAT): A risk based framework with goal to design and develop well understood processes that will consistently ensure a predefined quality at the end of the manufacturing process.

• Product quality and performance are ensured through the design of effective and efficient manufacturing processes.

• Product and process specifications are based on a mechanistic understanding of how formulation and process factors affect product performance.

• Continuous real time quality assurance through quality assessments of materials’ attributes and process controls.

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REAL TIME RELEASE TESTING

Real Time Release Testing: The ability to evaluate and ensure the quality of in-process and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls.

Process controls through measurements:

• at-line: Measurement where the sample is removed, isolated from, and analyzed in close proximity to the process stream.

• on-line: Measurement where the sample is diverted from the manufacturing process, and may be returned to the process stream.

• in-line: Measurement where the sample is not removed from the process stream and can be invasive or noninvasive. 68

REAL TIME RELEASE –EXAMPLE IN TABLETS

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FUTURE OF PHARMACEUTICAL QUALITY SYSTEM –

THE NEW APPROACH• Quality by Design (QbD): A systematic approach to

development that begins with predefined objectives and

emphasizes product and process understanding and process

control, based on sound science and quality risk management.

• Design Space: The multidimensional combination and

interaction of input variables (e.g., material attributes) and

process parameters that have been demonstrated to provide

assurance of quality.

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QUALITY BY DESIGN (QbD) – DESIGN SPACE

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QUALITY BY DESIGN (QbD) – DESIGN SPACE

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CONTINUOUS IMPROVEMENT OF PHARMACEUTICAL QUALITY

SYSTEM – PDCA CYCLE (E. Deming)Plan: QbD and QRM in

Pharmaceutical Development, and

set of Control Strategy

Do: Implementation of PAT

Check: Data analysis, SPC, Process

Capability Analysis, Trend analysis,

PQR, evaluation of effectiveness of

Control Strategy

Act: Decision for new Control

Strategy if necessary 73

NEW ROLES - CHALLENGES OF QAIN PHARMACEUTICAL INDUSTRY

• QA in the past was considered as “policeman”, “controller” and the “enemy” of production.

• QA should not be considered anymore as the absolutely responsible for quality of drug product.

• QA needs to perform a more pro-active role in improving the PQS by focusing much more in prevention and continuous improvement rather than appraisal of quality of drug product.

• QA should help top management and senior management to fulfill their responsibility to improve the PQS.

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• Traditional responsibilities and duties of QA can be enforced

and applied by periodic and effective audits. If other

departments are doing their work properly, then QA will be

able to significantly reduce its checking and oversight

activities.

• QA also needs to stop doing the work of other departments.

This will free up QA personnel to perform more proactive and

preventive type of activities, which would be more value-

added to the organization.

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• QA should adopt the use of quality risk management tools in

all processes, should determine the appropriate metrics and

data analysis tools, should determine the root causes of

problems and suggest appropriate CAPAs to improve

processes and product performance.

• QA, with the help of all departments, can suggest corrective

and preventive actions to senior management since senior

management has the capability to fix root causes.

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Finally, QA should assist senior management to built a “quality

culture” through the organization since “Quality is everyone’s

responsibility” (E. Deming).

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THANK YOU FOR YOUR ATTENTION

Any Questions ?

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THE ROLE OF QA IN PHARMACEUTICALS