1. 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.

2. Finished Pharmaceutical Product Manufacturing
World Health Organization
15 April, 2017
Manufacturing and marketing authorization
Pharmaceutical development
Formulation
Sites of manufacture
Manufacturing process
Manufacturing process controls of Critical steps and intermediates
Process validation and Evaluation
Next we will have a short session on Self-inspection.
We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject.
This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module.
We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions.
This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

3. Manufacturing site(s)
World Health Organization
15 April, 2017
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)
Next we will have a short session on Self-inspection.
We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject.
This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module.
We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions.
This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

4. Manufacturing Process
World Health Organization
15 April, 2017
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
Next we will have a short session on Self-inspection.
We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject.
This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module.
We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions.
This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

5. Manufacturing process (cont.)
World Health Organization
15 April, 2017
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.
Next we will have a short session on Self-inspection.
This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module.
We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions.
This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

6. Manufacturing Process Controls of Critical steps and Intermediates
World Health Organization
15 April, 2017
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
Next we will have a short session on Self-inspection.
We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject.
This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module.
We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions.
This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

7. Process Validation and Evaluation
World Health Organization
15 April, 2017
WHO validation definition
The documented act of proving that any procedure, process, equipment, material, activity, or system actually leads to the expected results.
Next we will have a short session on Self-inspection.
We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject.
This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module.
We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions.
This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

8. What should be validated ?
World Health Organization
15 April, 2017
“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”
Next we will have a short session on Self-inspection.
We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject.
This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module.
We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions.
This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

9. Purpose of Process Validation
World Health Organization
15 April, 2017
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
Next we will have a short session on Self-inspection.
We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject.
This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module.
We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions.
This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

10. Process Validation and Evaluation
World Health Organization
15 April, 2017
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
Next we will have a short session on Self-inspection.
We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject.
This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module.
We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions.
This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

11. 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#
Break lumps
Type of machine
Foreign matter contamination
Pre-Mixing (before wet granulation)
Mixing Time
Blend Uniformity
Mixing Speed
Mixing Volume
Mixing Method

12. Critical Steps to Validate (Example)
Manufacturing Step
CPPs
Impact on Quality
Wet Granulation
Load Size
Damp massing, API distribution, Torque
Mixing speed
Granulation Time
Binder amount
Damp Massing, Torque
Binder Concentration
Water Added
Feed rate
Ampere Meter
End Point Indicator

13. Critical Steps to Validate (Example)
Manufacturing Step
CPPs
Impact on Quality
Final Blending
Blending time
Blend Uniformity, size distribution, flowability
Blending Volume
Blending Speed
Lubricant/Disintegrant Sieve#
Glidant Sieve #
Blend Uniformity, size distribution, flowability, dissolution
Tabletting
Tabletting Speed
Assay, content uniformity, dissolution, physical and microbiological properties of tablets
Dwell Time
Hopper Level
Compression Force
Feeder Speed
IPC Adjustment
IPC Data

14. Identification of some CQAs (Tablets)
Quality Attributes (Final Blend, Tablets)
Impact on
Patient
Product
Process
Blend Uniformity and CU - C
Size Distribution
% Compressibility
LOD
Max. Hold Time
Appearance
Identification

15. World Health Organization
Process Validation and Evaluation Details required on first 3 production batches
World Health Organization
15 April, 2017
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
Next we will have a short session on Self-inspection.
We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject.
This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module.
We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions.
This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

16. World Health Organization
Other requirements
World Health Organization
15 April, 2017
Concurrent validation carried out during normal production on the first 3 consecutive production batches OR
For well-established processes process data, in-process controls and quality controls on a total of batches to present a statistically significant picture
Next we will have a short session on Self-inspection.
We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject.
This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module.
We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions.
This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

17. World Health Organization
Alternatives
World Health Organization
15 April, 2017
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.
Next we will have a short session on Self-inspection.
We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject.
This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module.
We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions.
This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

18. World Health Organization
Validation Protocol
15 April, 2017
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

19. 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

20. 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