Asean Guideline On Submission Of Manufacturing Process


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ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION

TABLE OF CONTENTS
1. INTRODUCTION..........................................................................................................................2 2. SCOPE ........................................................................................................................................2 3. DATA SUBMISSION REQUIREMENTS ......................................................................................2 4. CONTENT OF DEVELOPMENT PHARMACEUTICS ..................................................................3 5. CONTENT OF VALIDATION SCHEME .......................................................................................3 6. CONTENT OF VALIDATION REPORT........................................................................................4 7. NOTES ON RETROSPECTIVE VALIDATION & CONCURRENT VALIDATION.........................4 8. CHANGE CONTROL ...................................................................................................................5 9. TABLE OF CONTENTS OF PROCESS VALIDATION DOCUMENTATION................................5 10. QUALITY BY DESIGN AS AN ALTERNATIVE APPROACH TO PROCESS VALIDATION .......5 11. GLOSSARY .................................................................................................................................5 12. DOCUMENT VERSION HISTORY...............................................................................................5
ANNEX A1 GUIDANCE ON PROCESS VALIDATION SCHEME FOR SOLID ORAL DOSAGE PRODUCTS ANNEX A2 GUIDANCE ON PROCESS VALIDATION SCHEME FOR ASEPTICALLY PROCESSED PRODUCTS ANNEX A3 GUIDANCE ON PROCESS VALIDATION SCHEME FOR TERMINALLY STERILISED PRODUCTS ANNEX B TABLE OF CONTENTS OF PROCESS VALIDATION DOCUMENTATION ANNEX C GUIDANCE FOR QUALITY BY DESIGN AS AN ALTERNATIVE APPROACH TO PROCESS VALIDATION ANNEX D GLOSSARY
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GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
1. INTRODUCTION
Process Validation is a means of ensuring that manufacturing processes are capable of consistently producing a finished product of the required quality. It involves providing documentary evidence that key steps in the manufacturing process are consistent and reproducible. A validated manufacturing process is one that has been proven to do what it purports or is presented to do.
The term `validation’ is intended to apply to final verification at the production scale. Typically a minimum of three consecutive production batches should be successfully validated prior to the marketing of the product.
2. SCOPE
This guideline is intended to outline the regulatory requirements with respect to the manufacturing process validation studies which fall under the remit of drug registration and to guide the applicant in preparing the dossiers for the product license and post-approval variation applications. These requirements are not intended for regulating the manufacture of active substance and other starting materials, but intended to apply to data generated to evaluate or validate the manufacturing process of the finished product. For biotechnological and biological products, more extensive data may be required.
3. DATA SUBMISSION REQUIREMENTS
Option 1 - The data submission should include a validation report (see Content of Validation Report) on three consecutive successfully validated production batches.
Option 2 - In circumstances where submission of data on 3 consecutive production batches is not feasible at the time of application, the following can be submitted to DRA to obtain marketing approval.
Documents required: a) Development pharmaceutics report; and b) Validation data on 1 pilot batch with validation scheme on production scale batches.
In addition, the applicant is required to fulfill the following standard commitments:  To undertake that 3 consecutive full production batches are successfully validated before the
product is marketed, subject to concurrence by the DRA;  To submit the report to the Drug Regulatory Authority (DRA) within a specified time frame, or to
make the information from these studies available for verification post authorisation by DRA according to national procedure.
Note: Option 2 is not recommended for biological/biotechnological product, product manufactured using non standard method of manufacture, such as non-standard methods of sterilization and aseptic processing, and other specialized products such as modified release dosage form.
Option 3 - For products that have been approved by a reference agency, the applicant is required to provide a declaration statement to the effect that the same pre-approval dossiers pertaining to
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process validation that have been submitted to the reference regulatory agency are submitted to DRA for evaluation. Under certain circumstances where validation documents may not form part of the preapproval dossiers, the DRA may request for Validation Report or Validation Scheme. In addition, the applicant is required to undertake that 3 consecutive full production batches are successfully validated before the product is marketed and to submit the report to DRA upon request.
4. CONTENT OF DEVELOPMENT PHARMACEUTICS
The report on pharmaceutical development or development pharmaceutics should address the following:
a) Rationale for selecting the dosage form
b) Choice of product components (Active substance and excipients)  Compatibility considerations  Physico-chemical characteristics
c) Formulation of product  Use of overages  Effect of pH and other parameters  Effect of antioxidants, solvents, chelating agents, type/concentration of anti-microbial agents, etc  Stability, homogeneity and batch reproducibility considerations
d) Choice of manufacturing processes, including sterilization procedures
e) Choice of containers and packaging materials  Container-closure integrity  Sorption and leaching issues
f) Microbial attributes of dosage form
g) Compatibility of drug product with diluents or dosage device (e.g precipitation of drug substance in solution, sorption on injection vessels etc) throughout shelf life of drug product
The development pharmaceutics report should establish that the type of dosage form selected and the formulation proposed are appropriate for the intended (medicinal) purpose specified in the application for drug registration. It should also identify the formulation and processing aspects that are critical for batch homogeneity and reproducibility, and that hence have to be monitored routinely. The development pharmaceutics report (and the pilot batch report) should provide a link to the validation scheme proposed for the manufacture of production scale batches.
5. CONTENT OF VALIDATION SCHEME
Process validation scheme outlines the formal process validation studies to be conducted on the production scale batches. It should contain, but not limited to, the following information:
a) A description of the manufacturing process with a schematic drawing or flow chart b) A summary of the critical processes, control variables and justification for their selection c) Finished product specification (release)
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d) Details of analytical methods (reference to the dossier) e) In process controls proposed with acceptance criteria f) Additional testing intended to be carried out (e.g. With proposed acceptance criteria and analytical
validation appropriate) g) Sampling plan – where, when and how samples are taken h) Details of methods for recording and evaluation of results i) Proposed time frames for carrying out the studies j) Critical equipment/facilities to be used (for example, measuring/recording equipment together with
its qualification and calibration status)
6. CONTENT OF VALIDATION REPORT
The content of report should include, but not limited to the following information: a) Summary b) Introduction c) Batches (for example, date of manufacture, batch size) used for validation d) Manufacturing equipment e) Critical process steps and parameters f) Acceptance criteria g) Sampling plan h) Tabulation of the test results i) Batch Analysis j) Evaluation of data, including statistical process control analysis k) Evaluation of data including comparison against acceptance criteria l) Discussion on deviations and out of specification results m) Conclusion and recommendations
Where appropriate a description of the manufacturing process with a schematic drawing or flow chart may be required by the DRA.
Please refer to annexes listed below: a) Annex A1 for guidance on process validation scheme for solid oral dosage products, b) Annex A2 for guidance on process validation scheme for aseptically processed products and; c) Annex A3 for guidance on process validation scheme for terminally sterilized products.
7. NOTES ON RETROSPECTIVE VALIDATION & CONCURRENT VALIDATION
7.1 Retrospective Validation
For existing products already on the market for some time, retrospective validation may be performed. Retrospective validation involves the trend analysis (using control chart, etc) of historical manufacturing and QC data (eg. Results of assays, dissolution test, pH, SG, etc) of the product. Data from 10-20 batches of the product produced using the same stable manufacturing process should be analysed, to demonstrate that the manufacturing process is under control and `capable’. A Cpk (Process Capability) and/or Ppk (Process Performance) of 1.0, 1.33 and 2.0 represents a 3, 4, 6 sigma respectively. The measurement of Cp, Cpk, Pp or Ppk will be accepted as one of the statistical methods for analysing the process control.
7.2 Concurrent Validation In the case of orphan drugs, when the number of production batches per year is expected to be low, concurrent validation is acceptable. Other categories of drugs for which have short 4

lives (e.g. radiopharmaceuticals) and that are medically necessary (e.g. drug used to prevent or treat serious or life-threatening disease or medical condition, for which there is no other available source with sufficient supply of that drug or alternative drug available) may be considered on case by case basis. The applicant should seek prior consent from DRA before submitting the application to register any drug product that uses concurrent validation approach.
8. CHANGE CONTROL
Procedures are required to manage, plan and document the changes proposed in the manufacturing processes. Adequate supporting data should be generated to show evidence that the revised process would still ensure that the product meets the desired quality and approved specification.
Minor changes in SOP’s, environment, equipment etc are unlikely to require regulatory approval if they can be shown not to affect the quality of the finished product.
Other types of changes that would have significant impact on the quality of the finished product would require re-validation and prior regulatory approval. Such significant changes include changes to process (e.g. mixing times, drying temperatures, sterilization process), change of equipment that involves different design and operating parameters/principles. The applicant should submit appropriate supporting data for these changes.
9. TABLE OF CONTENTS OF PROCESS VALIDATION DOCUMENTATION
Annex B is a form that needs to be completed by the applicant for checking purpose.
10. QUALITY BY DESIGN AS AN ALTERNATIVE APPROACH TO PROCESS VALIDATION
Traditional approach in process validation focuses on three validation lots at commercial scale. Process validation is considered complete when the results of these lots are within acceptance criteria as defined in the validation protocol.
An alternative approach to traditional process validation is the continuous process verification, which adopts the concept of Quality by Design (QbD). It emphasizes on a life cycle approach where the process is continued to be verified even after the validation lots. Please refer to the Annex C for more details.
11. GLOSSARY
Annex D gives definitions of the terms used in the guideline.
12. DOCUMENT VERSION HISTORY
Version 1.0: Effective date on January 2005 Version 2.0: Draft version for 18th ACCSQ-PPWG meeting (Jun 2011) Version 3.0: Version adopted in 19th ACCSQ-PPWG meeting (Jul 2012)
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ANNEX A1 GUIDANCE ON PROCESS VALIDATION SCHEME FOR SOLID ORAL DOSAGE PRODUCTS TABLE OF CONTENTS
1. PURPOSE ...................................................................................................................................2 2. SCOPE ........................................................................................................................................2 3. GENERAL INFORMATION..........................................................................................................2 4. VALIDATION SCHEME OF SOLID ORAL DOSAGE MANUFACTURING PROCESSES ...........3
4.1. BATCH FORMULA …………………………………………………………………………….........3 4.2. MAJOR EQUIPMENT AND EQUIPMENT CLASS…………………………………………………….. 3 4.3. MANUFACTURING PROCESS DESCRIPTION AND PROCESS PARAMETERS……………………......5 4.4. SAMPLING PLAN AND ACCEPTANCE CRITERIA…………………………………………….....…… 7 4.5. HOLDING TIME FOR DRUG PRODUCTS…………………………………………………….......... 11 5. GLOSSARY .............................................................................................................................. 11
Annex A1 – Page 1

1. PURPOSE
This document is intended to provide guidance for the process validation scheme of the manufacturing process of solid oral dosage formulations.
This guidance document should be read in conjunction with the guidance listed below:  ASEAN Guidelines for Validation of Analytical Procedures  Current United States Pharmacopoeia, European Pharmacopoeia and Japanese Pharmacopoeia  Guidance for Industry, Process Validation: General Principles and Practices (FDA, January 2011)  CPG Sec. 490.100 Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval  SUPAC-IR: Immediate-Release Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (FDA, 1995)  SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral Dosage Forms Manufacturing Equipment Addendum (FDA, 1999)  SUPAC-MR: Modified Release Solid Oral Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation (FDA, 1997)  Dissolution Testing of Immediate Release Solid Oral Dosage Forms (FDA, 1997)
2. SCOPE
This guidance document applies to the solid oral dosage formulations – capsules, tablets and powder / granules for solution / suspension.
3. GENERAL INFORMATION
The presentations of solid oral dosage formulations are generally capsules, tablets and powder / granules for solution / suspension. Solid oral dosage products could be packaged as unit dosage form such as blisters and sachets or as multi units in the form bottles.
Capsules are solid dosage forms in which the drug is enclosed in a hard or soft soluble shell, commonly made of gelatine or starch or other suitable substance. Capsules may be formulated for immediate or modified release of drugs that may be in the form of powder, liquids or semisolids. Capsules can also be filled with uncoated or coated pellets, mini-tablets, powder or granules to permit transit through the stomach to the small intestine before the medication is released to alleviate potential problems of drug inactivation or gastric mucous irritation, as in the case of modified release dosage forms.
Tablets are solid dosage forms that contain medicinal substances with suitable excipients manufactured by direct compression of powders or granules with the application of high pressures, using steel punches and dies. Tablets can be of any size, weight, colour and shapes, and may have surface markings. Tablets can also be film-coated and/or have imprints.
Annex A1 – Page 2

Powder / granules for solution / suspension may be presented in single dose units or multi-dose units and is required to be reconstituted in water before being administered orally. Presentations in multidose units may be used where strengths of each dose may not be critical.
Process validation of a solid oral dosage form has to be specific to its batch formula and the operating principles of equipment used for its manufacture. The process parameters that need to be controlled and / or monitored and testing that need to be conducted during process validation of a bulk solid oral dosage formulations depend on its method of manufacture and its presentation (compressed tablet, coated tablet, capsule, powder / granule). The acceptance criteria should take into consideration the nature of the solid oral dosage, for example its drug release characteristics (immediate release (IR) or modified release (MR)). The following validation scheme can be used as a guide for process validation of solid oral dosage form and should be evaluated on a case-by-case basis.

4. VALIDATION SCHEME OF SOLID ORAL DOSAGE MANUFACTURING PROCESSES
The following items should be taken into account for the execution of process validation of the solid oral dosage manufacturing process:
4.1. Batch Formula For the execution of the manufacturing process validation, the batch formula of the solid oral dosage has to be well defined. All components of the dosage form to be used in the manufacturing process have to be listed, with their amounts on a per batch basis (including overages, if any).
4.2. Major Equipment and Equipment Class The major equipment, used for the manufacturing process, are to be identified and the class of each equipment be indicated. The equipment are broadly categorized by the unit operation (for example, blending and mixing, drying, particle size reduction, granulation, unit dosage, coating, encapsulation, printing, packaging). For each operation, the equipment is further categorized by class (operating principle).
The following lists some examples of equipment class for equipment of each major unit operation, which are non-exhaustive.

Equipment Mixing Tank Blender
Mill

Equipment Class
Convective mixers Diffusion blender (Tumble) Convective blender Pneumatic blender Fluid energy mill Impact mill Cutting mill Compression mill Screening mill Tumbling mill

Annex A1 – Page 3

Equipment Granulator
Dryers
Separators Tablet Press
Coating machine
Encapsulator (hard capsule)
Encapsulator (soft capsule)
Powder filler Blister packaging machine Bottle packaging machine

Equipment Class
Dry granulator Wet high-shear granulator Wet low-shear granulator Low-shear tumble granulator Extrusion granulator Rotary granulator Fluid bed granulator Spray dry granulator
Direct Heating, Static Solids Bed Direct Heating, Moving Solids Bed Direct Heating, Fluidized Solids Bed (Fluid Bed Dyer) Direct Heating, Dilute Solids Bed, Spray Dryer Direct Heating, Dilute Solids Bed, Flash Dryer Indirect Conduction, Moving Solids Bed Indirect Conduction, Static Solids Bed Indirect Conduction, Lyophilization Gas Stripping Indirect Radiant Heating, Moving Solids Bed (Microwave Dryer) Vibratory/Shaker Centrifugal Gravity Power assisted Rotary (centrifugal) Compression coating
Pan coating Gas suspension Vacuum film coating Dip coating Electrostatic coating
Auger Vacuum Vibratory Dosing disk Dosator
Positive displacement pump Gravity or force fed Mixers and Mixing Vessels Deaggregators Deaerators Holding Vessels
Vacuum Auger Plate-type
None identified

Annex A1 – Page 4

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Asean Guideline On Submission Of Manufacturing Process