Impact and Influence of Regulatory Changes to the Pharmaceutical Contract Manufacturing Market

Impact and Influence of Regulatory Changes to the Contract Manufacturing Market

An Australian case study

• Late January, 2003 serious adverse reactions were reported to the TGA by consumers of ‘Travacalm’

– Contract manufacturer was Pan Pharmaceuticals

– The product contained 200 micrograms of Hyoscine Hydrobromide (AI)


• 87 adverse reactions– Hallucinations– 19 people hospitalised

– Product sponsor was Key Pharmaceuticals who contracted Pan Pharmaceuticals to manufacture five batches, for the first time


• TGA testing revealed that the content of AI varied from 0% to 700% of all five batches involved

• The subsequent urgent audit of Pan Pharmaceuticals revealed that;– The wet granulation method of manufacture (as specified in

Marketing Authorisation) had not been used– Very poor mixing validation studies– The particle size of the Hyoscine Hydrobromide active

ingredient used by Pan was too large to be mixed uniformly throughout the batch


• Series of other citations – Elimination of out of specification results– Manipulation of HPLC data and records

– Subsequent recall of 1800 products– License suspension of Pan

Pharmaceuticals


• Contract manufacturing issues (contract acceptor)– Pan had deviated from the Marketing

Authorisation requirements during manufacture

– Pan did not communicate this or other out of specification results to contract giver

– No ‘authorised person’ checks that batches complied with the Marketing Authorisation


• Contract manufacturing issues (contract giver)– Key had not audited Pan– Key had not checked the quality of the

final product

– A ‘GMP agreement’ was in place

Impact and Influence of Regulatory Changes to the Contract Manufacturing

Market• Open your mind

– Figure 6

• It’s too simplistic to just speak in reference to the PIC/S GMP Chapter 7

• The Pharmaceutical industry demands more than this


Market• Contract manufacture and analysis

incorporated into a Quality Systems approach

• Nothing is ‘stand alone’– Validation– Quality Control– Quality Risk Management


Market• Build quality in

– Cannot test quality into a product

1. Management responsibilities2. Resources3. Manufacturing operations4. Evaluation activities


Market• Key concepts

– Quality– Quality by Design, product development– Quality risk management– CAPA– Change management– Quality unit– Inspection


Market• Management responsibilities

– Provide leadership– Structure organisation– Build a Quality System to meet

requirements– Establish policies, objectives and plans– Review the system


Market• Resources

– General arrangements– Personnel development– Facilities and equipment– Control outsourced operations


Market• Manufacturing

– Design, develop, document product and processes

– Examine inputs– Perform and monitor operations– Address non conformities


Market• Evaluation activities

– Analyse data for trends– Conduct internal audits– Quality risk management– CAPA– Promote improvement

Guidance for Industry – Quality Systems Approach to Pharmaceutical CGMP Regulations, U.S. Dept of Health and Human Services, FDA, September 2006

The new frontier – Quality Risk Management

• ICH Q9 Annex II, Potential Applications for Quality Risk Management

– Quality Risk Management as Part of Integrated Quality Management



– Regulatory operations– Inspections and assessment– Development– Facilities, equipment and utilities



– Materials management– Production– Lab control and stability studies– Packaging and labelling

Contract Manufacture and Analysis

• The system of Quality Assurance appropriate for the manufacturer of medicinal products should ensure that:– Medicinal products are not sold or supplied

before an Authorised Person has certified that each production batch has been produced and controlled in accordance with the requirements of the Marketing Authorisation and any other regulations relevant to the production, control and release of medicinal products


• Avoid misunderstandings

• Primary intent is that no product or work of unsatisfactory quality is manufactured– Defined– Agreed– Controlled


• Written contract (details commercial, contractual status)

• Duties and responsibilities – Qualified person responsible for batch

release has specific duties to fulfill


• Marketing Authorisation

• Change management



Contract giver

Contract acceptor

Contract itself


PDCA

Plan

Do

Check

Act

Contract giver

• Assess the competence of the contract acceptor

• Maintain GMP compliance, Marketing Authorisation requirements and technical requirements by means of the contract

• “...successfully”

Contract giver

• Full disclosure– Problems known that may pose hazards

• All information necessary

• Business benefits– Get it done right, the first time, every

time

Contract Acceptor

• Adequacy– Premises– Equipment– Knowledge and expertise– Personnel competence

Contract Acceptor

• Contract acceptors must hold their own Marketing Authorisation

• 3rd party agreements are prohibited without prior consent, evaluation and approval

• No adverse impact on product quality

The contract

• Specifies respective responsibilities

• Technical aspects– Pharmaceutical technology– Analysis of data– GMP– Marketing Authorisation requirements

The contract or a ‘GMP agreement’

• Can be acceptable to have a less formal ‘GMP agreement’ in the place of a contract

• A commercial contract and a linked and cross referenced GMP agreement– Cost disclosure

The contract or a ‘GMP agreement’

• Legally binding commercial contract– Price– Indemnity– Confidentiality clause requiring non

disclosure of the contract to any third party

– Using this methodology, only the GMP agreement would be shown to an auditor

Materials flow

• Materials– Received materials are fit for their

intended purpose– Meet their assigned acceptance criteria– Are released by a Qualified Person

– Contract giver must ensure that each batch received complies with specifications or has been released by an authorised person

Materials flow

• Qualified Persons responsibilities– Purchasing– Testing and release of materials– Production– Quality controls– Sampling and analysis

GxP critical documentation

• Records– Manufacturing– Analytical – Distribution

– Reference and retention sampling and documentation

Auditing

• The contract giver can visit and audit the contract acceptor’s facilities

• The contract acceptor may be subjected to regulatory audits

GMP requirements

• Counterfeiting

• Ongoing stability program– Monitoring stability post marketing– Extending stability to the end of the

product shelf life

What’s not covered in PIC/S GMP code chapter 7?

• Complaints and recalls• Stability testing• Reprocessing• Methodology of change control

• Retention periods for GxP records and retention samples

• Include these in your contracts or GMP agreements

ICH Q8 – Pharmaceutical Development

• ICH Q8 Pharmaceutical Development– Quality by Design

– The aim of Pharmaceutical Development is to design a quality product and its manufacturing process, to consistently deliver the intended performance of the product

ICH Q8

• This concept relies on a ‘lifecycle’ approach where knowledge evolves as experience with the product is realised

• ICH Q8 Pharmaceutical Development • ICH Q9 Quality Risk Management• ICH Q10 Pharmaceutical Quality System

ICH Q8

• Pharmaceutical Development relies on;- Knowledge from clinical phase studies

- Quality Risk Management

- Technology transfer to product development and manufacture

FDA – Pharmaceutical cGMPs for the 21st Century – a Risk Based Approach

• Thoroughly understanding the science behind manufacturing processes

• Greater manufacturing consistency by reduction and control of variables

• Leveraging new technologies

ICH Q8, Q9 and Q10

• Utilise Q8, Q9 and Q10 to;– Reduce the risk exposure to the

company posed by a lack of information

– Reduce the risk exposure to the customer posed by a lack of information

ICH Q8

• Operating within a design space

• Hidden sources of variability exist within any process– Assessment of these variables and their

impact on product quality

ICH Q8

Critical Quality Attribute (CQA)the characteristics that define product quality and feed directly in to Quality by Design

ICH Q8

Critical Quality Attribute (CQA)

– Quality attributes that must be controlled within pre defined limits

– Assurance that product meets its intended safety, efficacy, stability and performance

ICH Q8

Critical Process Parameter (CPP)a process parameter that must be controlled within pre defined limits

– Assurance the product meets its pre defined quality attributes

Continual improvement

• New technologies

• Communication

• Implementation using a lifecycle approach

Example of a

GMP Agreement for

contract manufacturing

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Example of a

GMP Agreement for


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Example of a

GMP Agreement for


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Example of a

GMP Agreement for


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Example of a

GMP Agreement for


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Date post:	08-Aug-2015
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