Oral solid dosage (OSD) manufacturing is a multifaceted process based on adherence to stringent regulatory guidelines, efficient workflow management, and uncompromising quality control measures. This article delves into the critical aspects of OSD manufacturing and the importance of understanding and implementing regulatory guidelines within the context of quality. It also explores the key considerations for manufacturing, emphasizing the need for a clear description of the process, technical justifications for any changes, and a comparative analysis of approved versus proposed processes.
The critical aspects of OSD manufacturing include:
· Chemical Documentation: This involves detailed information on the chemical properties of the drug substance, excipients, and the final product. It is essential to ensure that any changes in the chemical composition do not adversely affect the product's safety, efficacy, or quality.
· Manufacturing and Controls: Changes in the manufacturing process, equipment, or site can impact the product's quality. Maintaining stringent controls and validating any changes to the manufacturing process are crucial to ensure consistent product quality.
· In-vitro Dissolution Testing: This testing is critical to ensure that the drug’s release from the OSD is consistent and within specified parameters. Any changes to the formulation or manufacturing process that could affect dissolution rates must be thoroughly tested.
· In-vivo Bioequivalence: When changes are made to an OSD, it is necessary to demonstrate that the modified product is bioequivalent to the original product. This means the product must show the same bioavailability and therapeutic effect.
Key Regulatory Guidelines For OSD
· SUPAC-IR (scale-up and post-approval changes for immediate release solid oral dosage forms): This guidance provides a framework for managing changes in components, composition, manufacturing sites, batch sizes, and manufacturing processes for immediate release OSDs.
· SUPAC-MR (scale-up and post-approval changes for modified release solid oral dosage forms): Like the SUPAC-IR, this guidance addresses post-approval changes for modified release OSDs, including chemistry, manufacturing, and controls; in vitro dissolution testing; and in vivo bioequivalence documentation.
· Quality System Guidances, such as:
o Pharmaceutical Quality System/Quality System Guidances Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations (September 2006).
o Guidance for industry 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 (November 1995).
o Guidance for industry Nonsterile Semisolid Dosage Forms: Scale-Up and Post-approval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation (May 1997).
o Guidance for Industry, Process Validation: General Principles and Practices (FDA, January 2011).
o Dissolution Testing of Immediate Release Solid Oral Dosage Forms (FDA, 1997).
o FDA's Quality Systems Approach to Pharmaceutical cGMP Regulations (October 2006).
· Process Validation, such as:
o ASEAN Guidelines for Validation of Analytical Procedures.
o Current pharmacopoeias (e.g., United States Pharmacopoeia, European Pharmacopoeia, and Japanese Pharmacopoeia).
o FDA Guidance for Industry, Process Validation: General Principles and Practices.
o Health Canada's guidelines and Good Manufacturing Practices (GMP) regulations.
· ICH Guidelines: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) provides several guidelines relevant to OSD manufacturing, including Q8(R2), Pharmaceutical Development, Q7, Good Manufacturing Practice for Active Pharmaceutical Ingredients, and others that may apply depending on the specific changes.
It is important to consult the most recent versions of these guidelines and to engage with regulatory authorities early in the process of making changes to ensure compliance and facilitate a smooth approval process.
Production Management in OSD Manufacturing
A series of structured activities and processes is necessary to ensure that the production of tablets, capsules, and powders is carried out efficiently, safely, and in compliance with regulatory standards. Here are key aspects of workflow management in OSD manufacturing:
1. Batch Formula Management: The batch formula must be well defined before manufacturing begins. This includes listing all dosage form components, with their amounts on a per-batch basis. This ensures consistency and traceability in production.
2. Process Validation: A validation scheme should be followed to confirm that the manufacturing process produces a product meeting its predetermined specifications. This includes:
o Design Qualification (DQ): Ensure the design of the manufacturing process is suitable for its intended purpose.
o Installation Qualification (IQ): Verify that equipment and systems are installed correctly.
o Operational Qualification (OQ): Ensure the equipment and systems operate according to their operational specifications.
o Performance Qualification (PQ): Provide documented verification that the entire process operates within the anticipated operating ranges..
3. Dust Control and Cross-contamination: Special attention is required in the design, maintenance, and use of premises and equipment to control dust and prevent cross-contamination, which is critical in OSD manufacturing.
4. Pressure Cascade and Air Handling: Implement a pressure cascade system to ensure that air flows from areas of higher pressure to lower pressure, maintaining cleanroom standards and preventing contamination.
5. Point Extraction: Use point extraction systems to remove dust and maintain air quality, with the extraction point located as close as possible to the source of the dust.
6. Equipment and Facility Design: Design equipment and facilities to facilitate easy cleaning, maintenance, and efficient workflow. This includes the use of pass-through hatches or pass boxes to maintain segregation and pressure differentials between different manufacturing zones.
7. Manufacturing Process Development: Optimize the manufacturing process, including critical process parameters, to ensure consistent product quality. This involves understanding the impact of process changes on product performance and ensuring that any differences between clinical and commercial batches are well understood and justified.
8. Quality Control and Specifications: Establish release and shelf-life specifications for the OSD product, including in-process controls, dissolution profile testing, and ensuring that the product meets all quality criteria throughout its shelf life.
9. Documentation and Record-Keeping: Maintain thorough documentation, including batch records, validation reports, and change control records, to ensure traceability and compliance with regulatory requirements.
10. Regulatory Compliance: Adhere to guidelines and regulations set forth by regulatory bodies such as the U.S. FDA, including SUPAC guidelines for IR (immediate release) and MR (modified release) solid oral dosage forms, and ASEAN guidelines for manufacturing process validation.
11. Continuous Improvement: Implementing a system for continuous monitoring and improvement of the manufacturing process, including quality by design (QbD) principles and risk management strategies.
Comparative Analysis Of Approved Versus Proposed OSD Manufacturing Processes
In the pursuit of innovation and optimization within OSD manufacturing, it's imperative to adhere to stringent regulatory guidelines while striving for enhanced efficiency and quality. Here's a table that demonstrates the comparison between the approved and proposed manufacturing processes:
To summarize, manufacturing OSD forms requires rigorous adherence to regulatory guidelines, meticulous workflow management, and unwavering commitment to quality control. This article highlights critical aspects of OSD manufacturing, including regulatory compliance, workflow considerations, and quality imperatives. By adhering to guidelines such as the SUPAC and ASEAN and prioritizing factors like batch formula management and process validation, manufacturers can ensure the safe and effective delivery of medications to patients worldwide.
Oral solid dosage (OSD) manufacturing is a multifaceted process based on adherence to stringent regulatory guidelines, efficient workflow management, and uncompromising quality control measures. This article delves into the critical aspects of OSD manufacturing and the importance of understanding and implementing regulatory guidelines within the context of quality. It also explores the key considerations for manufacturing, emphasizing the need for a clear description of the process, technical justifications for any changes, and a comparative analysis of approved versus proposed processes.
The critical aspects of OSD manufacturing include:
· Chemical Documentation: This involves detailed information on the chemical properties of the drug substance, excipients, and the final product. It is essential to ensure that any changes in the chemical composition do not adversely affect the product's safety, efficacy, or quality.
· Manufacturing and Controls: Changes in the manufacturing process, equipment, or site can impact the product's quality. Maintaining stringent controls and validating any changes to the manufacturing process are crucial to ensure consistent product quality.
· In-vitro Dissolution Testing: This testing is critical to ensure that the drug’s release from the OSD is consistent and within specified parameters. Any changes to the formulation or manufacturing process that could affect dissolution rates must be thoroughly tested.
· In-vivo Bioequivalence: When changes are made to an OSD, it is necessary to demonstrate that the modified product is bioequivalent to the original product. This means the product must show the same bioavailability and therapeutic effect.
Key Regulatory Guidelines For OSD
· SUPAC-IR (scale-up and post-approval changes for immediate release solid oral dosage forms): This guidance provides a framework for managing changes in components, composition, manufacturing sites, batch sizes, and manufacturing processes for immediate release OSDs.
· SUPAC-MR (scale-up and post-approval changes for modified release solid oral dosage forms): Like the SUPAC-IR, this guidance addresses post-approval changes for modified release OSDs, including chemistry, manufacturing, and controls; in vitro dissolution testing; and in vivo bioequivalence documentation.
· Quality System Guidances, such as:
o Pharmaceutical Quality System/Quality System Guidances Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations (September 2006).
o Guidance for industry 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 (November 1995).
o Guidance for industry Nonsterile Semisolid Dosage Forms: Scale-Up and Post-approval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation (May 1997).
o Guidance for Industry, Process Validation: General Principles and Practices (FDA, January 2011).
o Dissolution Testing of Immediate Release Solid Oral Dosage Forms (FDA, 1997).
o FDA's Quality Systems Approach to Pharmaceutical cGMP Regulations (October 2006).
· Process Validation, such as:
o ASEAN Guidelines for Validation of Analytical Procedures.
o Current pharmacopoeias (e.g., United States Pharmacopoeia, European Pharmacopoeia, and Japanese Pharmacopoeia).
o FDA Guidance for Industry, Process Validation: General Principles and Practices.
o Health Canada's guidelines and Good Manufacturing Practices (GMP) regulations.
· ICH Guidelines: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) provides several guidelines relevant to OSD manufacturing, including Q8(R2), Pharmaceutical Development, Q7, Good Manufacturing Practice for Active Pharmaceutical Ingredients, and others that may apply depending on the specific changes.
It is important to consult the most recent versions of these guidelines and to engage with regulatory authorities early in the process of making changes to ensure compliance and facilitate a smooth approval process.
Production Management in OSD Manufacturing
A series of structured activities and processes is necessary to ensure that the production of tablets, capsules, and powders is carried out efficiently, safely, and in compliance with regulatory standards. Here are key aspects of workflow management in OSD manufacturing:
1. Batch Formula Management: The batch formula must be well defined before manufacturing begins. This includes listing all dosage form components, with their amounts on a per-batch basis. This ensures consistency and traceability in production.
2. Process Validation: A validation scheme should be followed to confirm that the manufacturing process produces a product meeting its predetermined specifications. This includes:
o Design Qualification (DQ): Ensure the design of the manufacturing process is suitable for its intended purpose.
o Installation Qualification (IQ): Verify that equipment and systems are installed correctly.
o Operational Qualification (OQ): Ensure the equipment and systems operate according to their operational specifications.
o Performance Qualification (PQ): Provide documented verification that the entire process operates within the anticipated operating ranges..
3. Dust Control and Cross-contamination: Special attention is required in the design, maintenance, and use of premises and equipment to control dust and prevent cross-contamination, which is critical in OSD manufacturing.
4. Pressure Cascade and Air Handling: Implement a pressure cascade system to ensure that air flows from areas of higher pressure to lower pressure, maintaining cleanroom standards and preventing contamination.
5. Point Extraction: Use point extraction systems to remove dust and maintain air quality, with the extraction point located as close as possible to the source of the dust.
6. Equipment and Facility Design: Design equipment and facilities to facilitate easy cleaning, maintenance, and efficient workflow. This includes the use of pass-through hatches or pass boxes to maintain segregation and pressure differentials between different manufacturing zones.
7. Manufacturing Process Development: Optimize the manufacturing process, including critical process parameters, to ensure consistent product quality. This involves understanding the impact of process changes on product performance and ensuring that any differences between clinical and commercial batches are well understood and justified.
8. Quality Control and Specifications: Establish release and shelf-life specifications for the OSD product, including in-process controls, dissolution profile testing, and ensuring that the product meets all quality criteria throughout its shelf life.
9. Documentation and Record-Keeping: Maintain thorough documentation, including batch records, validation reports, and change control records, to ensure traceability and compliance with regulatory requirements.
10. Regulatory Compliance: Adhere to guidelines and regulations set forth by regulatory bodies such as the U.S. FDA, including SUPAC guidelines for IR (immediate release) and MR (modified release) solid oral dosage forms, and ASEAN guidelines for manufacturing process validation.
11. Continuous Improvement: Implementing a system for continuous monitoring and improvement of the manufacturing process, including quality by design (QbD) principles and risk management strategies.
Comparative Analysis Of Approved Versus Proposed OSD Manufacturing Processes
In the pursuit of innovation and optimization within OSD manufacturing, it's imperative to adhere to stringent regulatory guidelines while striving for enhanced efficiency and quality. Here's a table that demonstrates the comparison between the approved and proposed manufacturing processes:
To summarize, manufacturing OSD forms requires rigorous adherence to regulatory guidelines, meticulous workflow management, and unwavering commitment to quality control. This article highlights critical aspects of OSD manufacturing, including regulatory compliance, workflow considerations, and quality imperatives. By adhering to guidelines such as the SUPAC and ASEAN and prioritizing factors like batch formula management and process validation, manufacturers can ensure the safe and effective delivery of medications to patients worldwide.
GMP refers to the Good Manufacturing Practice regulations promulgated by the US Food and Drug Administration under the authority of the Federal Food, Drug, and Cosmetic Act (See Chapter IV for food, and Chapter V, Subchapters A, B, C, D, and E for drugs and devices.) These regulations, which have the force of law, require that manufacturers, processors, and packagers of drugs, medical devices, some food, and blood take proactive steps to ensure that their products are safe, pure, and effective.
GMP regulations require a quality approach to manufacturing, enabling companies to minimize or eliminate instances of contamination, mixups, and errors. This protects the consumer from purchasing a product which is not effective or even dangerous. Failure of firms to comply with GMP regulations can result in very serious consequences including recall, seizure, fines, and jail time.
GMP regulations address issues including record keeping, personnel qualifications, sanitation, cleanliness, equipment verification, process validation, and complaint handling. Most GMP requirements are very general and open-ended, allowing each manufacturer to decide individually how to best implement the necessary controls. This provides much flexibility, but also requires that the manufacturer interpret the requirements in a manner which makes sense for each individual business.
GMP is also sometimes referred to as "cGMP". The "c" stands for "current," reminding manufacturers that they must employ technologies and systems which are up-to-date in order to comply with the regulation. Systems and equipment used to prevent contamination, mixups, and errors, which may have been first-rate 20 years ago may be less than adequate by current standards.
本文针对了一个具体安例，来说明灯检机Knapp测试的详细方法和数据的计算方式。
灯检机Knapp测试的主要应用是为了比较全自动灯检机与人工灯检的精度差异。Knapp测试使用同一套测试集进行，先采用人工目检进行检测，再使用全自动灯检机进行检验，通过计算Knapp效率来进行评估，若Knapp效率等于或大于100%，则全自动灯检机的检测效果等同于或优于现有的人工灯检。
首先，开始进行Knapp测试之前，我们需要为每种类型的产品和每种尺寸的产品准备一个测试集。在这个案例中，测试集包括250个不可见的标记容器。
为何要做不可见的标记呢？因为如果不这样，操作员就知道哪种缺陷在哪个容器上了。因此，通常我们使用UV墨水或二维码进行标记。在这250个容器中，有200个应该是合格产品，占测试集的80%。另外50个应为有缺陷的产品，有缺陷的容器需要从公司的缺陷库中选择出来的。
接着，我们应挑选至少5名操作员，他们的检验能力应该与工厂的标准检验能力相当。每个操作员必须对准备好的批次进行10次检验。专门用于检验每个容器的时间，必须与标准灯检过程中使用的时间相同。检验结果将被记录在一个表格中，如下图所示：
图1：Knapp测试人工检验结果记录表
让我们用容器100号来举例。容器100号被操作员1号检验了10次，被操作员2号和操作员3号都检验了10次，等等。
· 操作员1号在10次检验中9次检出了这个容器的缺陷
· 操作员2号在10次检验中7次检出了这个容器的缺陷
· 操作员3号在10次检验中8次检出了这个容器的缺陷……
那么在下一步，我们需要确定容器100号的人工检验的质量系数（FQ）。我们可以简单地将检验到的检出数加起来，然后除以总检验数，再乘以10。
在上图种你能看到公式：9+7+8+10+8=42。
就是说一共100号容器被检测出了42次。我们把它除以50个总检验数，再乘以10。
100号容器的人工检验质量系数（FQ）：42÷50×10=8.4
这里我这里我们得到100号容器的质量系数是8.4。
接着，质量系数需要在参考表格中进行查询，表格分为三个区：
接收区——这里显示绿色；
灰色区以及剔废区——也就是被认定为的“不合格区”
你需要将相应的质量系数记录在表格中。
接着我们来到自动灯检机的测试环节，也就是需要去证明其检测效果。对于全自动视觉检验，同样的原则也应适用于此。
在通过循环模式对测试组进行10次检验后，所有被剔废的容器数量必须也记录在下面的表格中。当然，在这里自动检验的质量系数应该在表格中列出。
最终的Knapp效率是由自动检验质量系数值的总和，除以人工检验质量系数值的综合计算而出。
图2：Knapp测试机器检验结果记录表
接下来我们可以比较这两个表格。只有当人工检验的质量系数（FQ）大于或等于7的数值，处于剔废区，才会被计算为自动检验的参考值，用于计算Knapp效率。
该案例中，人工检验中大于7的质量系数的总和是53，而自动检验的质量系数的总和是57。将二者相除，即可得到的Knapp效率也就是是107.5%。
Knapp效率：57÷53=107.5% (机器÷人工)
如果Knapp效率大于或等于100%，则自动灯检系统的视觉配置已通过Knapp测试，也就意味着机器检验优于人工检验。
A Knapp test is carried out to ensure that the manual inspection is similar to the automated process of inspection. It is a very lengthy process, but this document is generally asked for if you qualify an automated machine for inspection by an auditor.
The Knapp test is as follows:
Firstly, the USP states “all parenterals will be 100% visually inspected.”
Secondly, below are my opinions only (experience) and if I fail to identify anything that a regulator may be looking for, or if someone with more experience can add to anything or correct anything, I will truly value the feedback.
When developing a method in which to qualify operators it is important to develop a process for qualifying that you can easily defend.
The following discussion is something we can call the ‘pseudo Knapp method’
The PDA presents papers on Julius Knapp’s methodology to use when validating a semi-automated inspection method (eg. HAWKEYE SHANDONG) or fully automated inspection machines (eg. HAWKEYE SHANDONG) so these can be used for reference.
The best thing to do is collect particulate rejects from various batches (keeping the characteristics of the product the same – eg. viscosity, clear or yellowish, fill volume, etc…)
After collecting X numbers of particulates rejects from various batches, these vials can be blindly placed into Y number of uninspected vials from various batches.
Now with X + Y, have inspectors (let’s say three different inspectors) manually inspect these vials 10 times each (3 inspectors times 10, times each vial, is 30 inspections each vial) . Using Knapp’s probabilistic methodology, anything with a probability of 0.7 is classified as a reject.
Thus from the X + Y, any vials that were rejected 21 out of 30 times would be considered a reject. Using these vials classified as rejects and using vials that are classified as good vials (anything with a probability of 0.3 and less) a standard qualification set can be created.
Note: it is best to get reject vials that have a reject probability of 1.0 (30/30) to make things easier in the end.
Let’s say for example we create a set of 100 vials with 30 vials being rejects, and 70 being good vials classified per Knapp’s probabilistic model.
Other terms that need to be defined include:
RZE – Reject Zone efficiency = sum of reject probability of the 30 reject vials / 30 reject vials
RAG – Reject Accept/Grey = sum of probability of rejecting the 70 Accept and Grey vials / 70 vials
NOTE: I did not discuss grey vials, don’t see a need but this can be incorporated
Now we should determine the RZE of the set. Adding up the probabilities of rejection from the 30 reject vials, (eg. let’s say its 28) Thus the RZE = 28/30 = 0.93. J. Knapp states that an RZE of 0.80 and 0.95 is what is normally seen in industry, so determine an RZE that suits your business, also your business would also want a low RAG (RAG should be less than 0.10, but is also based on what you sets RAG is) which is considered how your operators will react to good product.
Now you can test your operators using this set and calculate the RZE and RAG values to identify operators for inspection.
After writing this, I know that there are many things that have been left out, for example, you need to verify the visual accuracy of your inspectors (eye test done during hiring). In addition, your product set may degrade over time causing it to form particulates so you may need to store the set at the product requirements to impede degradation, or replace the set on an on-going basis.
I would be most grateful for any other comments on this subject.
目 录
第一部分 检测方法原理及设备、样品信息
1. 检测方法及原理
1.1 检测方法
1.2 检测方法原理
2. 检测依据
3. 在线检测及样品信息
3.1 检测设备
3.2 药品基本信息
3.3 阳性样品信息
第二部分 高压放电检漏方法开发
1. 阳性样品的制备
2. 方法学开发
2.1电压筛选
第三部分 检测方法验证
1. 阳性样品的制备
2. 准确度验证
2.1 样品准备
2.2 检测结果
3. 耐用性研究
3.1 检测速度的耐用性研究
3.2 高压电压的耐用性研究
详情 请致电 13589838190
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