Some Future Developments

Brian Carlin, Ph.D FMCChris Moreton, Ph.D FinnBrit Consulting

IPEC-Americas FDA Seminar, October 21, 2013

1

Presentation Outline

• Variable pharmaceutical product batch size

• Continuous manufacture of finished pharmaceutical products

• Formulation flexibility

2

Variable Pharmaceutical Product Batch Size

• How do we achieve this without compromising validation?

• Use the manufacturing methods and equipment for continuous processing, but in a batch manufacturing setting:– Fixed lots of components pre-assigned and pre-

dispensed:• API• Excipients

– Change in product batch size simply means varying the processing time.• Running for longer does not change the validation of a

continuous process equipment train.– Final release would be a combination of in-process

controls (PAT) and testing, and finished product testing.– No differences in traceability/batch recall.

3

Continuous Manufacture of Finished Pharmaceutical

Products• Continuous manufacture of finished pharmaceutical

products is a logical extension from a combination of Quality by Design and Process Analytical Technology.

• Components are released to a specification– API– Excipients

• May require additional characterization• Added to hoppers and used without pre-dispensing.• Starting components are continually fed into the equipment

train, and product is continually produced, packed and moved to storage.

• Samples would be taken and tested according to a pre-approved sampling plan.

• There would also be in-process controls (PAT)• Finished product lot numbers would be assigned on the

basis of a time of output, or a quantity of output.

4

Issues for Continuous Manufacture of Pharmaceutical

Finished Products• Batch number assignment.• Frequency of sampling and testing.• Final batch release.• What happens if the process fails at

some stage.• Starting component adulteration.• Traceability/recall.

5

Batch number assignment

• The batch number will represent a defined output from the equipment train.

• Two ways:– Set time of output (e.g. 24 hours, 168 hours)– Set quantity of output (e.g. 100,000 units, etc.)

• Either will work, but we need to understand which is being used, and have sufficient records to know when components were added and product was removed.

6

Frequency of sampling and testing

• This depends on the process and equipment train, the PAT instrumentation and what is being measured, the extent of end-product testing required to meet Agency expectations, the risk to the patient, and the cost to the manufacturer.

• This will form part of the control strategy, and will be linked back through the Design Space to the level of understanding.

7

Final release

• For final release to occur the batch will need to be assessed:– Manufacturing and control records assessed:

• Starting components are within specification.• Process parameters are within the limits set out in the

Design Space/Control Strategy.• In-process control results are within the required limits• Final testing results are within the required limits.• Manufacturing yield is within limits for a set batch time, or

manufacturing time is within limits for a set batch quantity.• Quantity of reject material is acceptable.• The batch remains within the Design Space, and thus the

Control Strategy remains valid.

8

Process failure

• How do we deal with process or equipment failure?– Understand how the process works and what can go

wrong, and what the likely outcomes may be in terms of final product control and release.

– Undertake a controlled shut down of the downstream processing from the point of failure.

– Investigate the failure and determine the likely root cause.

– Clear, repair/replace and clean the equipment train.– Execute a controlled start-up according the standard

process operating procedure.

9

Starting component contamination/adulteration• How do we deal with contamination/adulteration of a

starting component that is found after the material has been added to the feed hopper?– Understand the risk:

• Is the material out of specification on a physical parameter (e.g. wrong particle size or viscosity grade), or is it contaminated with another material (e.g. diethylene glycol/ ethylene glycol in glycerin or propylene glycol)

– Once contaminated material is added to the feed hopper, the whole of the contents of that feed hopper are deemed contaminated.

– Stop the process, empty the hopper and discard the contents, clean down the hopper and the equipment train, recharge the hopper, and restart the process according to the established procedures.

– We need to determine how much product has become adulterated:• We need to understand the nature of the processing, the

throughput of the equipment train, the capacity of any hoppers, and the amount of material in the equipment train at any given time.

• We will have a record of when the material was added to the hopper.

10

How can we prevent and reduce the impact of

contamination/adulteration incidents?

• Total control of starting components:– Know your supply chain, including the manufacturing

site, and any intermediaries.– Proper testing and control.

• Going beyond the pharmacopeia monograph will likely be necessary.

• Reduce the amount of material held in the feed hoppers:– Replenish the feed hoppers more frequently rather than

less frequently, e.g. on a daily basis.• Limits the amount to be discarded.

11

Traceability/recall• If there are no pre-dispensed starting

components, and if there is no predefined product batch, how do we deal with traceability in the event of a recall?– Define a batch as a set output, and this may change as

more experience is gained with the product/equipment train.

– If a problem is found, then all output from after the last ‘passing’ sample is deemed to have failed, together with everything up to the next ‘passing’ sample.

– If the process seems to oscillate between pass and fail, then it is not operating in an adequate state of control.• Requires in-depth investigation, and likely a re-design of

the formulation and/or process.

12

Formulation flexibility

• What do we mean by formulation flexibility?– The quantitative composition of different batches may

vary within an agreed Design Space.– The qualitative composition of different batches could

also vary within an agreed Design Space:• But this is less likely!

• Why would we need formulation flexibility?– To compensate for changes in starting components.

• For example, addition of variable amounts of a wetting agent in response to changes in hydrophobicity of an API.

– To compensate for variability within the process.• For example, varying the amount of magnesium stearate in

response to changes in the granule particle size distribution.

13

Note!

• The flexibility must be part of the Design Space and Control Strategy.

• The Design Space and Control Strategy must be agreed with the Agency ahead of time, i.e at the time of approval of the marketing application or supplemental application.

• The marketing application would need to be consistent with the relevant Guidance documents.

14

Conclusions

• QbD together with PAT can provide the basis for more flexibility in pharmaceutical product manufacture.

• At the same time, they can also provide the basis for moving to truly continuous pharmaceutical product manufacturing (24/7 and up to 50 weeks per year).

• Formulation flexibility based on an established Design Space can also be envisaged

15

On-going Dialog• Hopefully, this workshop has provided FDA with a good

basic understanding of Excipient Variability and it’s impact on QbD as well as the realistic limitations of what can be provided as far as samples for design space development and the alternative approaches under investigation.

• IPEC hopes this workshop will be the beginning of an on-going dialog between FDA and IPEC on excipient QbD.

• IPEC wants to be a resource for FDA on any excipient related issues where our expertise would be useful.

16www.ipecamericas.org

Possible Topics for Discussion

• What benefits can industry derive from an increased use of excipient QbD concepts?– Regulatory recognition of supplier-user partnerships

jointly reducing excipient-related risks through mutual due diligence.

• FDA OGD’s experience from the implementation of QbR for generic drug applications.

17www.ipecamericas.org

Thank you!

We will now take questions!

18www.ipecamericas.org

Panel discussion Q&A

19www.ipecamericas.org