progress and challenges of parametric release applied to pharmaceuticals · 2014-07-29 · progress...

Progress and challenges of parametric release

applied to pharmaceuticals

Humberto Zardo, BS Ind Pharm, MSc

Consultant – Irvine, CA - USA

II Symposium SINDUSFARMA / ANVISA / FIP-IPS

New Frontiers in Manufacturing Technology, Regulatory Sciences and Pharmaceutical Quality System

Parametric release

1. What is it?

2. Why it is needed?

3. Requirements / Challenges

4. Sterility assurance

5. Risks and critical control points

6. System operating range and limits setting

7. Questions and answers

H. Zardo – Parametric Release – 2 of 19 –

What is parametric release?

• “A system of release that gives the assurance that the product is of the intended quality based on information collected during the manufacturing process and on the compliance with specific GMP requirements related to Parametric Release.”

Ref.: European Organization for Quality ; PIC/S PI 005-5 (2007) & PE 009-10 annex 10 (2013); ISPE Glossary of Pharmaceutical and Biotechnology Terminology

• The UK Medicines Control Agency (MCA) already recognizes the principle of parametric release and the concept of the move from final product testing to good process control.

Ref.: TRILL, A., An MCA inspection perspective on innovation , Pharm Eng 22(2), 2002

• “Parametric release may be authorised for certain specific parameters as an alternative to routine testing of finished products. Authorisation for parametric release should be given, refused or withdrawn jointly by those responsible for assessing products together with the GMP inspectors.”

Ref.: PIC/S PE 009-10 annex 10 (2013) section 2.2


Need of parametric release

• To release items that are at risk if sampled upon receiving, e.g., sterile components (APIs, excipients, primary container / closure), hazardous products, highly sensitive items, etc. 14.1 – “All incoming materials and finished products should be quarantined immediately after receipt or processing, until they are released for use or distribution.”

• To release materials on “as needed basis”, reducing the risk of contamination while handling and sampling 14.12 – “If one delivery of material is made up of different batches, each batch must be considered as separate for sampling, testing and release.”

• To comply with the requirement that only released materials be used 14.15 – “Only starting materials released by the QC department and within their shelf-life / retest date should be used.”

Ref.: WHO TRS 961 (45th Report) 2011, annex 3, sections 14.1; 14.12, 14.15


Requirements for parametric release

• Detailed description of the process

• Risk analysis and identification of critical control points (CCP)

• Process validation

• Process monitoring (on each lot)

– Bioburden

– Endotoxins

– Controls on-line, in-line, at-line, off-line

• Good documentation practices

• History of good compliance with GMP

• Authorization Ref.: WHO TRS 961 (45th Report) 2011, annex 6; TRS 908 annex 7; ICH Q8, Q9, Q10; PIC/S PE 009-10


Challenges Changes required (will take time to overcome difficulties and cause impact):

– Knowledge – Attitudes – Individual behavior – Group behavior

Ref.: Hersey, P & K Blanchard, Management of Organizational Behavior, 4th Ed., Prentice-Hall, 1982

Explain and educate: – Meeting the assessor/inspector prior to make submissions as a proactive

approach to provide the basis for mutual understanding of the technology and underlying application philosophy to enable regulators to make informed judgments regarding the validity of the approach.

Ref.: TRILL, A., An MCA inspection perspective on innovation , Pharm Eng 22(2), 2002

Locate strategic vendors: – Critical to meeting company objectives – Long term, collaborative, high strategic values – Frequently used – Proactive QA and Operations

Ref.: DUMONT, F. & ONORATO,S. Establishing and managing a vendor network for clinical and supply manufacturing services, Pharm Eng 33(3), 2013


Parametric release & sterility

From WHO’s CGMP for sterile pharmaceutical products :

• Quality control: “In those cases where parametric release has been authorized in place of sterility testing special attention should be paid to the validation and the monitoring of the entire manufacturing process.”

• Manufacture of sterile preparations - “For parametric release systems, bioburden assay should be performed on each batch and considered as an in-process test. Where appropriate, the level of endotoxins should be monitored.”

• Quality Management – Release procedure of finished products: “statement on whether the control strategy employs process analytical technology (PAT) and/or real-time release or parametric release.”

Ref.: WHO TRS 961 (45th Report) 2011, annex 6, sections 2.3; 4.36; Annex 14, Appendix: Content of a site master file, section 2.2


Sterility assurance system

The sum total of the arrangements made to assure the sterility of products. For terminally sterilized products these arrangements typically include the following stages: • Product design • Knowledge and control (if possible)

of starting materials and process aids • Control of the contamination of the process of manufacture

(cleaning, sanitation of wet surfaces, suitable clean rooms or isolators, process time control limits, and filtration)

• Prevention of mix-ups between sterile and non-sterile product streams • Maintenance of product integrity • Sterilization process • Totality of Quality System

(written procedures, release checks, change controls, training, preventive maintenance, failure mode analysis, validation calibration, prevention of human error, etc.)

Ref.: PIC/S PI 005-3 (2007) – Recommendation on “Guidance on parametric release”


Risk identification

Systematic use of information to identify hazards referring to the risk question or problem description

Information can include:

Material attributes

Process variables

Quality attributes

Risk identification addresses the question, “What might go wrong?” including identifying the possible consequences

Risk identification provides the basis for science-based validation plans and other steps in the quality risk management process

Ref.: Adapted by H. Zardo from POTTER, Christopher -PQLI ISPE webinar, 2012


Example of decision tree for CCPs at each step Injectable – Liq

Step CP

CC

P

Receiving

Weighing

Solution

1st Filtration

2nd Filtration

Filling / Stopper

Capping

Labeling / Cartoning

Storage

Question 1 Do control preventative measure(s) exist? Yes Q2; No: Is control at this step necessary for safety? Yes Modify step, process or product; No Not CCP Proceed to next step

Question 2 Is the step specifically designed to eliminate or reduce the likely occurrence of a hazard to an acceptable level? (**)

Yes CCP; No Q3

Question 3 Could challenges with identified hazard(s) occur in excess of acceptable level(s) or could increase to unacceptable levels? (**)

Yes Q4; No Not CCP Proceed to next step

Question 4 Will a subsequent step eliminate identified hazard(s) or reduce likely occurrence to an acceptable level? (**)

Yes Not CCP stop; No CCP Legend: CP = Control point; CCP = Critical control point (**) Acceptable and unacceptable levels need to be defined within the overall objectives in identifying the CCPs of HACCP plan. Ref.: CAC-RCP-1-1969 Rev4-2003


Qualification and validation GMP for sterile pharmaceutical products

• Sanitation

– Detergents, disinfectants, fumigation, rotating schedule

• Manufacture of sterile products

– Grade A: aseptic preparations and filling; UDAF; background Grade B

– Grades C & D: less critical stages of the manufacturing

• Terminal sterilization

– Moist or dry heat, irradiation, or gases

– Bioburden and sterility assurance level (SAL); time elapsed production-sterilization

• Aseptic processing

– Control and mitigation of risks

• Sterilization by filtration

– Types of filters

• Finishing of sterile products

– Closure of containers: caps, fusion, crimp, use of vacuum or inert gases

• Technologies

– Isolator, Restricted Access Barriers (RABS), Blow-Fill-Seal (BFS), etc. Ref.: WHO TRS 961 annex 6, 45th Report, 2011


Design of experiments (DoE) What is DoE? • Provides distinction between major factors and minor factors (process inputs) • Can also identify where interactions exist • Allow for optimization of a process • Lead to a robust process

Inputs: – Raw materials – Process settings – Others?

Outputs: – Process response – Product response

Methods: – Full factorial – Half fractions – Other partial factorial – Screening designs – Response surface (RSM)

Ref.: J. Moore, Suppliers Quality Systems, Ethicon Endo-Surgery, Jan 2001


System operating ranges

Ref.: WHO Technical Report Series 961, 45th Report, 2006 – Annex 5, Fig 28

Action limit

Action limit

Alert limit Alert limit

Design set-point condition

Normal operating range

Operating range – validation acceptance criteria

Compendia absolute limits


Where is parametric release used?

In my practice: • Chemical synthesis / purification of intermediates and

semi-finished APIs

• Gamma irradiated APIs, excipients, and primary container/closures

• Receiving of materials for production of parenterals. Samples for invasive identification and local or regional regulatory requirements are collected when the “packs” are opened for compounding and/or processing a batch. Batch release depends of successful completion of tests on starting materials, bulk and finished product.

Ref.: Speaker notes


Progression from QC to QA

3. Quality assurance (QA) Ensure continuous status of compliance / qualification

2. Quality management system (QMS)

Support / infrastructure Trends

1. Quality control (QC): Sample, inspect, measure / compare Accept = Conform, or Reject

Ref.: ICH Q8, Q9 and Q10; WHO TRS 908, 929, 937, 953, 957 and 961; PIC/S PE 009-9, ISO 2839, 13408, etc.


Check the current status: Regarding parametric release

Current knowledge To be improved Resources needed


Perguntas / Questions


Obrigado

Thanks

Merci

Grazie

Gracias

谢谢

[email protected]

Speaker

Humberto Zardo – Senior consultant, training instructor and advisor in management & improvement of manufacturing operations. Former Technical Director of Allergan Pharmaceuticals (Brazil & USA) and Program for Appropriate Technologies in Health (USA). Industrial Pharmacist (Federal University of Paraná – Curitiba, PR – Brazil). Training in International Business and Materials Engineering. Master in Science in Biochemistry-Pharmaceutical Technology (University of São Paulo – S. Paulo, SP – Brazil). Member of ISPE – USA.

e-mail: [email protected]


progress and challenges of parametric release applied to pharmaceuticals · 2014-07-29 · progress...

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