applying gmp to continuous processes: challenging the...

Applying GMP to Continuous Processes: Challenging the Batch

Mentality

Dr Iain MooreChair GMP Committee IPEC Europe

Croda Europe Ltd

Applying GMP to Continuous Processes: Challenging the Batch Mentality• International Pharmaceutical Excipients Council• Founded in 1992 • Sister organisations in United States (IPEC-

Americas), Japan (JPEC), and from July 2008 China (IPEC-Brasil in development)

• Collectively IPEC: www.ipec.org• A unique association of Excipient Manufacturers,

Suppliers and Users• Global membership exceeds 200 companies

http://www.ipec.org/

http://www.ipec-europe.org/index.php

Applying GMP to Continuous Processes: Challenging the Batch Mentality

• What is GMP?• Continuous Processes• Applying GMP to Continuous

Processes

What is GMP?

• “Good Manufacturing Practice is that part of Quality Assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the Marketing Authorisation or product specification. “Part 1 EU GMP

What is GMP?

• A short History of GMP• Thalidomide• The “Orange Guide”• Focus on finished dosage forms• ICH Q7

What is GMP?

• EU Part I GMP Introduction finishes with• “It is recognised that there are acceptable

methods, other than those described in the Guide, which are capable of achieving the principles of Quality Assurance. The Guide is not intended to place any restraint upon the development of any new concepts or new technologies which have been validated and which provide a level of Quality Assurance at least equivalent to those set out in this Guide.“

• Forgotten, ignored or too risky to do otherwise?

What is GMP?

• The detailed rules in the legal definitions of GMP reflect the technology used to make the product

• What suits batch manufacturing does not suit continuous processing• The technology is different

• So the existing rules of GMP may not apply or be useful in protecting the patient• Therefore we need new rules, and to prepare new rules we

have to understand the principles of GMP and apply those to the new situations

What is GMP?

• A personal definition of GMP• ..that part of Quality Assurance that

ensures the manufacturing process stays within the design space (ICH Q8) and is operated through the application of a set of controls that arise from a comprehensive Quality Risk Assessment (ICH Q9) process. These controls should be sustained in a robust Quality Management System (ICH Q10) and adhere to the principles of GMP.

What is GMP?

• So what are the principles of GMP?• A personal view:

• The product should not harm the end user• The product should be pure and free from

contaminants• There should be defined manufacturing

procedures which have been proven to be effective in making product of a consistent quality

What is GMP?

• Core Principles ii• There should be records of the manufacturing

process that demonstrate that the product has been made in accordance with these planned arrangements

• Personnel should be competent in the execution of their roles and have sufficient training

• Manufacturing equipment should be fit for purpose and maintained in that condition

• You cannot inspect quality into the final product



Processes

Continuous Processes

• Very common technology when the scale of the chemistry is very large

• Can have significant safety and process control benefits over batch operations

• Major area of scientific advancement with microfluidic processes


• Key Differences with Batch processes• Lower raw material costs• Less waste• Better energy efficiency• Safer and with better control (Temp Press,

mixing etc)• Better quality of product• No beginning or end• Materials recycled• Blending


• Simple Batch Process schematic

E-1

E-2 E-3

P-1

P-2

P-6

RAW MATERIALS

PACKING LINE

REACTION VESSEL


• Simple Continuous Process schematic


• Key benefits are associated with the very close control of the critical process conditions (chemistry and physics) which can mean a higher quality product• Microfluidic (“lab on a chip”)

devices now mean this approach is no longer limited to Petrochemical scale operations



Processes

Applying GMP to Continuous Processes

• Publications• IPEC-PQG GMP Guide

2006• Based on

• IPEC GMP Guide 2001 &• PQG PS 9100 –a

certificatable standard• Published in USP as

<1078>, 2006 version of guide just out in Pharmacopoeial Forum


• Remit of 2006 edition was to include guidance for excipients made by continuous processes

• The specific inclusions on this subject will be reviewed

• By no means a comprehensive list of differences or factors to consider


• Definitions• Batch/lot

• A specific quantity of material produced in a process or series of processes so that it can be expected to be homogeneous. In the case of continuous processes, a batch may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval.


• A related and important GMP concept is scale of manufacture

• What does this refer to in terms of continuous processing?• Significant changes in the design space

• Mass and heat transfer rates • Flow rates• Final lot size


• Is the change of scale significant?• Quality risk assessment• Consider impact on impurities

• Increased? Reduced? New?• Thermal history of product

• Degradants• Purification Processes

• Changed efficiencies• It is possible that we may see very large

changes in scale that are not material to product quality


• 6.3.2 Equipment • Equipment used in the production,

processing, packaging, testing or storage of an excipient should be maintained in a good state of repair and should be of suitable size, construction and location to facilitate cleaning, maintenance and correct operation, depending on the type of processing (for example batch versus continuous).


• 6.3.2 Equipment • So what is suitable for batch

processing may not be suitable for continuous processing

• But it still has to be maintained, and be of a construction that does not adversely affect the excipient


• 7.5.1.1 Production Instructions and Records

• For batch processes an accurate reproduction of the appropriate master production instructions should be issued to the production area. For continuous processes a current processing log should be available.



• Records should be available for each batch of excipient produced and should include complete information relating to the production and control of each batch. For continuous processes the batch and its records should be defined (for example based on time or defined quantity).

• Suitable controls should be in place for the preparation and issue of a batch record for batch processing and/or a production record, log sheet or other appropriate documentation for continuous processing,



• Recognition that the style of recording batch history is different.

• Discrete records vs lengthy log books including electronic records

• Key issue is to ensure the critical control parameters that define product quality are within the control space limits• Important that there is a deviation system that can alert the

quality unit during a campaign that there has been a significant deviation

• Important that the design space is well defined so that the impact of such deviations on product quality are understood

• The product may not have been diverted into separate storage but into the main storage facility – knowledge of the impurity profile when made under abnormal conditions becomes critical


• 7.5.1.1 Production Instructions and Records • The batch should be homogenous within

the manufacturer’s specifications. This does not necessitate the final blending of continuous process material if process controls can demonstrate compliance to specifications throughout the batch.• But if Off spec material is known to have been

produced and added to the bulk storage then homogeneity should be demonstrated


• 7.5.1.2 Equipment Cleaning• For continuous processing the

frequency of equipment cleaning should be determined by the manufacturer and justified.• Would need evidence that the equipment is

not being fouled by build up of residues• Cross contamination issues should be less

significant


• 7.5.2. Validation• A long time ago in BS5750 the concept that

product quality could not always be tested in was recognised – so called “special processes”• Tablet hardness is a good example

• Thus control of the manufacturing process alone was the only assurance of product quality

• This is the origin of ISO 9001 term “validation”


• 7.5.2. Validation• Continuous processes can fall into this

category, especially where sampling of the bulk product may not identify inhomogeneities• So application of Design and Control space

principles in ICH Q8 are more important• Basic scientific understanding of the

process and how variations impact product quality are also critical

• Can be challenging to gather this data in a structured manner


• 7.5.2. Validation• For Continuous processes validation

means defining the design and control spaces

• Unlikely to do that on the basis of operational “experiments” alone

• Pilot plant and lab demonstration plants become more important – but note comments on scale of operation


• 7.5.3 Traceability• Quality-critical items should be clearly identified

and traceable through records. These records should allow traceability of the excipient both upstream and downstream. Identification of raw materials used in batch production processes should be traceable through the batch numbering system or other appropriate system. Identification of raw materials used in excipients produced by continuous processing should indicate the timeframe during which a particular batch of raw material was processed through the plant.


• 7.5.3 Traceability• Bulk tanks make traceability uncertain for

continuous and batch processes • The organisation should define how it

will effect traceability through bulk tanks• Usually adopt either “infinite dilutions” or

“perfect segregation”


• 7.5.3 Traceability – Infinite Dilutions

• Lot 1 goes into the tank and is used

• Lot 2 tops up the tank with 10% of lot 1 remaining

• There is perfect mixing• How much of lot 1 is in the

tank after 6 refills?E-26 E-27

LOT 1

LOT 1 AND LOT 2

PERECTLY MIXED


• 7.5.3 Traceability – Infinite Dilutions• Fill 1 100%• Fill 2 10%• Fill 3 1%• Fill 4 0.1%• Fill 5 0.01%• Fill 6 0.001% (10 ppm)• At which point is the contribution from Fill 1

insignificant?


• 7.5.3 Traceability – Perfect Segregation

• Lot 1 is added to the Tank• Use of Lot 1 is registered until

100% of the delivery is consumed

• Then Use of Lot 2 is started, regardless of when it was added• Assumes perfect separation of

Lot 1 and Lot 2


• 7.5.3 Traceability – Infinite Dilution or Perfect Segregation

• Which is better?• Perfect mixing for me because SAP R/3

reports traceability using this approach!


• 7.5.3.2 Inspection and Test Status• There should be a system to identify the

inspection status of quality-critical items including raw materials, packaging materials, intermediates and finished excipients. Whilst storing materials in identified locations is preferred, any means that clearly identifies the test status is satisfactory. Continuously-fed materials may need special consideration in order to satisfy these requirements.


• 7.5.3.2 Inspection and Test Status• Not too helpful but an alert that the

issue needs to be addressed using non- traditional methods• Segregated storage for in spec and out of

spec material• Tank status logs and quarantine systems• All the more important that quality critical

process parameters are monitored regularly and used to determine lot status – real time in process testing


• 8.2.4.2 Finished Excipient Testing and Release

• For excipients produced by continuous processes assurance that the excipient conforms to documented specifications may be achieved through the results of in-process testing or other process control records.• Process validation is more important than

for batch processes


• 8.2.4.2 Finished Excipient Testing and Release

• Final batch testing may not offer as much confidence of lot quality as batch manufacturing

• PAT and real time monitoring will be much more important


• 8.3 Control of Non Conforming Product• Handling out of specification material –

from a continuous process • Reprocessing (going through same steps

again)• Reworking – using new processes

• Both should adhere to the existing guidance for batch processes – the key issues here are can new impurities etc be introduced?


• Conclusions• Continuous processing is different• Requires careful consideration of the GMP

rules• If they do not seem sensible don’t apply them• But think about the issues of product quality

that they are trying to control• Use Q8 and Q9 to develop new GMP controls

suitable to provide a high degree of assurance of product quality

Applying GMP to Continuous Processes: Challenging the GMP

Batch Mentality

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