the control system and its life-cycle - the regulators

Control Strategies and Specifications

The Control System and Its Life-Cycle - The Regulators Expectation and Vision

Nanna Aaby Kruse,Senior Biological Assessor, Member of BWP and BMW

Danish Medicines Agency

CMC Strategy Forum Europe 2011,Barcelona, 21-23 March

Nanna Aaby Kruse, Danish Medicines Age2

Agenda• Legislation and guidance outlining issues relating to

control strategy• How, where and when to control• Regulatory expectations

Key Message• QbD is not mandatory• QbD opens up for new thinking. ”Everything” is up for

discussion, - including the control system.• The more QbD approach – the more we (Assessors)

need to know in the dossier on the ”philosophy” of the control system chosen for a given Company


A Control Strategy is mandatory

• GMP, Directive 2003/94/EC, Article 11– …… Manufacturer shall establish and

maintain a quality control system…..


Specification• According to ICH Q6B a specification is defined as

– A list of tests

– References to analytical procedures

– Appropriate acceptance criteria

• ” Specifications establish the set of criteria to which a drug substance, drug product or materials at other stages of its manufacture should conform to be considered acceptable for its intented use.”

• Specifications apply at many levels– Raw materials

– In-process controls (process and/or product)

▫ Monitor the performance of the process

– Drug Substance- Drug Product and stability data

▫ Confirm the that predefined attributes are met


• Basis for setting the specification according to ICH Q6B– Characterisation data

– Levels qualified in clinical and pre-clinical studies

– Normal production levels

– Stability data

• An established link between physicochemical properties and clinical data is the most valuable basis for justifying a specification

Specification, cont.


Specification, cont.Specifications are one part of a total control strategy

designed to ensure product quality and consistencyControl of raw andstarting materials

Control of cellsubstrate & cell bank

In ProcessControls

Control of DS and DP (characterization,

specification, stability)

Validatedmaufacturing

process

Goodmanufacturing

Practice

TOTAL TOTAL QUALITY QUALITY CONTROLCONTROL

Kowid Ho, Afssaps, Mats Welin, MPA

Impact o

n safety and efficacy

Impact o


Impact o



EUROPEAN PHARMACOPOEIA:

Directive 2003/63/EC, introduction and general principles:

• “….(5) With respect to the quality part (chemical, pharmaceutical and biological) of the dossier, all monographs including generalmonographs and generals chapters of EP are applicable…”

HOWEVER;

“Regulatory flexibility” in mentioned in the Pharmacopoeia, 1. GENERAL NOTICES 7/2010:10000

• “This does not imply that performance of all the tests in a monograph is necessarily a prerequisite for a manufacturer in assessing compliance with the Pharmacopoeia before release of a product. The manufacturer may obtain assurance that a product is of Pharmacopoeia quality from data derived, for example, from validation studies of the manufacturing process and from in-process controls…..


Quality system (ICH Q10)

• By virtue of Article 2 of Directive 2003/94/EC and Directive 91/412/EEC manufacturing authorisation holders are already obliged to establish and implement an effective pharmaceutical quality assurance system in order to comply with Good Manufacturing Practice (GMP)…. This apply when a product is marketed.

• ICH Q10 gives the possibility to develop: • A pharmaceutical quality system designed for the entire

product lifecycle and therefore goes beyond current GMP requirements…. OPTIONAL


ICH Q8, Q9 and Q10 offers possibility…

• … to use a systematic approach to evaluate and use experience from the very first development to the establishment of the final manufacturing process, in the control of a proper product quality….

• This opens up for the possibility to design a control system perfectly fitted for the product and its process…

– Build quality into the product…


Control Strategy (ICH Q8(R))… DRUG PRODCT• A control strategy is designed to ensure that a product of

required quality will be produced consistently…

• Describe and justify

– how in-process controls and the controls of input materials (drug substance and excipients),

– intermediates (in-process materials),

– container closure system,

– drug products

contribute to the final product quality.

• These controls should be based on product, formulation and process understanding and should include, at a minimum, control of the critical process parameters and material attributes.


Product lifecycle

Pharmaceutical development &Manufacturing experience

Design Space &Control Strategy

Prior knowledge &Continuous process

VerificationTrend analysis

Defining QTPPIntended use in clinicoute of administration

Dosage formDelivery systemDosage strength

…..

Defining CQAAggregate

Oxidised formsDeamidated forms

HCP, DNA…..

Control of input material attributesValidation

In- Process ControlReal time Release Testing

Release testing

Process and product Understanding

Identifying sources ofViability

Quality Risk Management


Control Strategy (ICH Q8(R)), cont.

• A comprehensive pharmaceutical development approach will generate process and product understanding and identify sources of variability.

• Understanding sources of variability and their impact on downstream processes, in-process materials, and drug product quality can provide an opportunity to shift controls upstream and minimise the need for end product testing


Control strategy• Is a specification necessary if using the advance

development approach??• A specification has to be established and each batch of a

product should comply to it• Necessary for stability studies and establishment of shelf-

life• Necessary for Official Medicines Control Laboratory

(OMCL) control

• QbD vs Q6B vs EP is not in disagreement, but When/if tested, a given product or material must comply with its approved specification


In conclusion so far:• A quality control system should be established • Drug substance, drug product and shelf-life specifications are

requested• Compliance with EP, ICH Q6B is requested, but when/if tested,

a given product or material must comply with its approved specification

Within the framework of ICH Q8, Q9 and Q10 it is relevant to ask– What to control?– How to control?– Where to control


What to control?• ICH Q8 is dedicated to Drug Product…..• Control of input materials:

– Drug substance..

– Raw materials

– Excipients

– Primary packaging materials

• The process - Critical Process Parameters• The product - Critical Quality Attributes

– But what about the non-critical CQA and CPP??

– Should they be part of the dosser or not???

– What if CQAs and/or CPP change during development??

– How much can be controlled via IPC-testing?

– Is a control strategy site or product specific?


How to control?• Best available and suitable method !

• Off-line analysis• In-line analysis• PAT• Real Time Release Testing


Where to control? – Drug substance• Case by Case, - as justified by process development,

understanding of process and product relationship, quality risk management and the control strategy applied……….

• Validation vs In-process controls vs Drug Substance Release??– Protein content?– pH?– Bioburden?– Impurities?– Potency?– Glycosylation?– Purity – Monomer and Aggregates?– Endotoxin?– Identity?


Where to control? – Drug Product• Case by Case, - as justified by process development,

understanding of process and product relationship, quality risk management and the control strategy applied……….

• Validation vs In-process controls vs Drug Product Release ?????– Protein content?– pH?– Extractable volume?– Excipients content?

– Purity – Monomer and Aggregates??– Particulate matter??– Endotoxin??– Sterility??

– Identity???


The Regulators Expectation and Vision

• ICH Q8, Q9 and Q10 is developed to achieve (even) better designed and controlled manufacturing processes for medicinal products

– Flexibility

• QbD is NOT mandatory• Lots of challenges for industry and regulators

– Agreement of terminology and definitions

– Level of appropriate / relevant information to be include in a dossier

• We have to realise that a mixture of traditional and enhanced approach will be the fact for a long time

• Product lifecycle change of the control system is foreseen / expected

• An ”invitation” from industry to Assessors to get familiar with the individual overall control strategy chosen for a given Company


Thank you for your

Attention

the control system and its life-cycle - the regulators

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