1. MANUFACTURING PROCESS AND VALIDATION
Rutendo Kuwana
Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

2. Finished Pharmaceutical Product Manufacturing
World Health Organization
World Health Organization
Finished Pharmaceutical Product Manufacturing
19 April, 2017
19 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. 2

3. Manufacturing site(s)
World Health Organization
World Health Organization
Manufacturing site(s)
19 April, 2017
19 April, 2017
Name and street address of each facility where any aspect of manufacture occurs including production, sterilisation, packaging and quality control
Blocks and Units should be clearly stated
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. 3

4. Development of manufacturing process
Pre- formulation
Formulation
Pilot manufacture
Industrial Scale 4

5. Development of manufacturing process
Relationship between method of manufacture and process validation data
Process should address the need and value of in process controls
Process evaluation and validation should justify reduction of some tests from routine 5

6. Development of manufacturing process
Scale Up Data
Used to generate information from laboratory through pilot to production scale batch
Evidence that scale up will not result in loss in quality
Should show that variations in batch size will not adversely alter FPP characteristics 6

7. Manufacturing process Information required
Flow diagram
critical steps – 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, temp, pH
Environmental conditions, e.g. rel. humidity for hygroscopic FPPs. 7

8. Manufacturing process (2)
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
Data for ≥ 3 full scale batches to show achievement of predetermined specifications 8

9. Manufacturing process Controls of critical steps and intermediates
Acceptance criteria (justified)
Test methods (cross reference acceptable)
Intermediates isolated during process e.g tablet cores in film-coated tablet production
Acceptance criteria (justified if not Compendial) 9

10. Manufacturing Process Controls of Critical steps and Intermediates
Acceptance criteria
Methods
Test Item
Manufacturing step
99-110%
By weighing
Yield
After Step 1.1 %
After Step 1.2
98-100%
After Step 2.1.3
After Step 2.2.3
See table below
Visual inspection
Appearance
After Step 3.2 -
Thickness
In-house
Average mass
Eur. Ph.
Hardness
≤1%
Eur. Ph
Friability
≤15min
Disintegration time
97-100%

11. Manufacturing Process Controls of Critical steps and Intermediates
100/270mg Tablets
Test Item mg
Average Mass – Layer 1 mg
Average Mass - layer 1+2
Round, biconvex, bilayered tablet; one layer is yellow coloured and may be mottled, and the other one is white to slightly yellow, with a break line, engraved "GP" on one side, and "100" on the other side
Appearance mm
Thickness
>100N
Hardness

12. Process Validation and Evaluation
World Health Organization
World Health Organization
Process Validation and Evaluation
19 April, 2017
19 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.
Process validation is the collection and evaluation of data, from process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products
US FDA
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. 12

13. Process validation & evaluation
Differentiate between the following generics:
New FPPs (new for manufacturer, not marketed yet)
FPPs that have been newly developed by the manufacturer, though it will be a generic
Full validation required
Established FPPs
The manufacturer has manufactured & marketed this FPP for quite some time
Submit review of report for ≥ 10 recent consecutive batches
Manufactured within the preceding year. If less than 10 batches, may extend the period to 3 years
result/trend/statistical analysis & discussion
Rejected batches excluded - submit failure investigation 13

14. What should be validated ?
World Health Organization
World Health Organization
What should be validated ?
19 April, 2017
19 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. 14

15. Purpose of Process Validation
World Health Organization
World Health Organization
Purpose of Process Validation
19 April, 2017
19 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. 15

16. Process Validation and Evaluation
World Health Organization
World Health Organization
Process Validation and Evaluation
19 April, 2017
19 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. 16

17. World Health Organization
Process Validation and Evaluation Details required on first 3 production batches
19 April, 2017
19 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. 17

18. Validation “new” product Concurrent / prospective validation (1)
Concurrent validation
Carried out during normal production
First 3 production batches (prospective validation)
In-process controls are set on outcome of validation
Extensive sampling and testing during process, for example (tablets)
planned sampling on mixing / granulation stages for content uniformity (low-dose FPPs & FDCs !)
A large number of tablets for mass and/or content uniformity, hardness, friability and even dissolution
Sampled according to plan during process
Statistical analysis of results with conclusions
To be within acceptance criteria 18

19. Validation “new” product Concurrent / prospective validation (2)
Parenteral products, aseptically filled (if terminal sterilization is not possible)
Filling ampoules with culture media, then
Incubation and control of microbial growth
Level of contamination: ≤ 0.1%
Challenge experiments to determine
robustness of process
effect of material variations, such as particle size can be carried out on experimental batches e.g. stability of granulate over time
Effect in case of unplanned stoppage 19

20. Validation “new” product Concurrent / prospective validation (4)
Laboratory scale batches (small size),
To support e.g. formulation and packaging development
Pilot batches
Used e.g. in stability and safety/efficacy studies
Size for oral solid dosage forms: the largest of 10% of production scale or 100,000 units
Productions scale
For full validation and stability studies
Scale-up / scale down after registration
Up to10-fold compared to the original batch size (minor amendment/change) 20

21. Process Validation Data
Compliance with FPP specifications alone inadequate to demonstrate validation of processes and control over process
Manufacturer may not have completed formal validation on production scale batches
Important to link development and evaluation of laboratory and pilot scale batches, process development and optimisation 21

22. Data should be available for verification post - registration
Development of manufacturing process Process Validation Scheme/Protocol
To be used for applications where production scale batches not yet produced
To outline the formal validation process to be conducted on production scale batches (at least 3 consecutive batches)
Data should be available for verification post - registration 22

23. Development of manufacturing process Process Validation Scheme/Protocol (2)
Information required
- short description of the process including critical processing steps or parameters to be monitored
- FPP release specifications
- Details of analytical methods
- IPC proposed and acceptance criteria
- additional testing and analytical validation
- sampling plan – where, when and how samples are taken
- details of methods for recording and evaluating of results
- proposed timeframe 23

24. Development of manufacturing process Process Validation Report
After validation
Batch analytical data
Certificates of analysis
Batch manufacturing records
Report on unusual findings, modifications or changes found necessary with appropriate rationale
Conclusions
Significant deviations to be informed to DRA and regulatory approval required before implementation 24

25. World Health Organization
Other requirements
19 April, 2017
19 April, 2017
For well-established processes/product for the manufacturer – report on review of NLT 10 batches manufactured in the past 12 months
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. 25

26. Review report for established FPP should contain at least the following
List of reviewed batches - batch numbers, manufacturing dates and batch size. Any differences from the prequalified/approved batch size should be clarified.
Review of starting materials (active pharmaceutical ingredients (APIs) and excipients) – list of sources (API), compliance with specifications
Review of primary packing materials used in the FPP, including reference to those from new sources.
A tabulation of Batch Analysis data (including in-process test results and finished product quality control results) together with statistical and trend analysis where appropriate.
A review of all out-of-specification and related investigations, with indication of batches that failed to meet specification(s)
A review of all deviations.
All changes carried out
Quality-related returns, complaints and recalls.

27. World Health Organization
Alternatives
19 April, 2017
19 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. 27

28. Analytical Methods
Process knowledge depends on accurate and precise measuring techniques on starting material, intermediates and finished product.
For data to be of value the analytical tests must be scientifically sound
Validated analytical methods are not required during product and process development activities. The methods should however be scientifically sound (e.g. specific, sensitive, accurate), suitable and reliable for the specified purpose.

29. Use of analytical methods - generics
Pharmaceutical
Clinical
At initial phase of pharmaceutical development
To understand the profile of related substances and to study stability and start measuring the impact of key product and manufacturing process parameters on consistent FPP quality
To develop a stable and reproducible formulation for the manufacture of bioequivalence, dissolution, stability and pilot-scale validation batches
To determine bioavailability in healthy volunteers
At advanced phase of pharmaceutical development
To be robust, transferable, accurate, and precise for specification setting, stability assessment, and QC release of prequalified batches
To optimize, scale-up, and transfer a stable and controlled manufacturing process for the prequalification product
To prove bioequivalence after critical variations to the prequalified dossier