Manufacturing Process

Rutendo Kuwana Technical Officer, WHO, Geneva

Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda.

Finished Pharmaceutical Product Manufacturing

Manufacturing and marketing authorization Pharmaceutical development Formulation Sites of manufacture Manufacturing process

Manufacturing process controls of Critical steps and intermediates

Process validation and Evaluation

2|

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Manufacturing site(s)
Name and street address of each facility where any aspect of manufacture occurs including production, sterilisation, packaging and quality control
Including any alternative manufacturers

Certificate issued by the Competent DRA according to WHO Certification scheme for each site where a major step of manufacturing is performed Valid GMP certificate (may not insist if inspected by WHO)

3|

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Manufacturing Process
Flow chart with indication of each step showing where materials enter the process. Indication of critical steps and in-process controls Description of manufacturing/packaging including
Scale Equipment by type (e.g. tumble blender) & working capacity Process parameters for steps, (e.g. time, temperature, pH) Environmental conditions, e.g. relative humidity for hygroscopic FPPs., area class for sterile FPPs

4|

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Manufacturing process (cont.)

Proposal for reprocessing justified with data. Copy of master formula.

Batch manufacturing record real batch.

Sterile products sterilisation steps and/or aseptic procedures. Description of in-process tests including plan of sampling and acceptance limits). Data for 3 full scale batches to support achievement of predetermined specifications.

5|

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Manufacturing Process Controls of Critical steps and Intermediates

Identification of critical steps with test methods and justified acceptance criteria Information on quality of isolated intermediates, test methods and justified acceptance criteria to control them

6|

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Process Validation and Evaluation

WHO validation definition

The documented act of proving that any procedure, process, equipment, material, activity, or system actually leads to the expected results.

7|

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

What should be validated ?

Any aspect of operation, including significant changes to the premises, facilities, equipment or processes, which may affect the quality of the product, directly or indirectly, should be qualified and validated

8|

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Purpose of Process Validation

Process validation is intended to establish that the proposed manufacturing process is a suitable one and yields consistently a product of the desired quality. i.e. that the process is suitable and under control

9|

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Process Validation and Evaluation

Validation is mandatory for processes including all critical steps
The aim is to show that critical steps are under control and lead continuously to the desirable quality

Examples of critical steps (list non exhaustive)

mixing, coating, granulation, emulsification, non-standard sterilisation
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

10 |

Critical Steps to Validate (Example)

Manufacturing Step CPPs Impact on Quality

API

Particle Size

Product Dissolution

Different lots (same source) Challenge study RAM sieving MESH# Type of machine Pre-Mixing (before wet granulation) Mixing Time Mixing Speed Mixing Volume Break lumps Foreign matter contamination Blend Uniformity

Mixing Method

11 |

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Critical Steps to Validate (Example)

Manufacturing Step Wet Granulation Load Size Mixing speed Granulation Time Binder amount Binder Concentration Water Added Feed rate Ampere Meter End Point Indicator Damp Massing, Torque CPPs Impact on Quality Damp massing, API distribution, Torque

12 |

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Critical Steps to Validate (Example)

Manufacturing Step Final Blending CPPs Blending time Blending Volume Blending Speed Lubricant/Disintegrant Sieve# Impact on Quality Blend Uniformity, size distribution, flowability

Glidant Sieve #

Blend Uniformity, size distribution, flowability, dissolution

Assay, content uniformity, dissolution, physical and microbiological properties of tablets

Tabletting

Tabletting Speed Dwell Time Hopper Level Compression Force Feeder Speed IPC Adjustment

IPC Data

13 |

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Identification of some CQAs (Tablets)

Quality Attributes (Final Blend, Tablets) Impact on Patient Product Process

Blend Uniformity and CU Size Distribution

% Compressibility LOD Max. Hold Time Appearance Identification

C -

C C
C C C C C

C
C C C -

14 |

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Process Validation and Evaluation Details required on first 3 production batches

Batches batch number batch size place and date of manufacture batch number of API(s) yield batch purpose (validation, stability, clinical trial ) Process equipment process parameters validation protocol. Results critical steps in process control finished product specification
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

15 |

Other requirements
OR For well-established processes process data, in-process controls and quality controls on a total of 10- 25 batches to present a statistically significant picture

Concurrent validation carried out during normal production on the first 3 consecutive production batches

16 |

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Alternatives
If validation data (on production scale batches) are not available submit

validation protocol,
commitment that validation report will be submitted later for evaluation, commitment that data will be available in case of inspection,

commitment that WHO will be informed of any significant deviation.

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

17 |

Validation Protocol
Objective, Scope and Rationale Brief description of the process with summary of critical steps and parameters to be followed during validation, process flow chart specifications and analytical methods of the FPP at release, details of analytical procedures and limits, List of equipment to be used

sampling plan and acceptance criteria

Defined CPPs to be monitored and CQAs to be tested proposed timeframe

Validation report when submitted should include results for each batch, certificates of analysis, batch production records, report on unusual findings, modifications, observations and conclusions
18 |
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Validation Report Outline Each Batch

Objective Scope Validation Batch Information Deviation report Critical Quality Attributes (CQAs) Test Data

Statistical Evaluation of CQAs

Conclusion

NB: One batch, One Report

19 |
Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda

Validation Report Outline Final

Objective Scope Validation Batch Information Summary Summary on CQAs and Test Data evaluated Overall Conclusion

Recommendation
NB:Three Batches, One Report

20 |

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda