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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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

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

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.

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 10- 25 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.

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.

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

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

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