◆ Can the (√n+1) Rule be accepted in Sampling Plans?? (04-Apr-18 ECA)
Is a sampling plan based on the (√n+1) rule acceptable for determining the correct number of samples? The Canadian health authority (Health Canada) listed this question in the section “Good Manufacturing Practices (GMP) Questions and Answers” of their website and answered it as follows:
Sampling plans and procedures must be statistically valid and based on scientifically sound sampling practices.
Among the important issues to be considered regarding the risks are:
A sampling plan based on (√n+1) may generally be acceptable, e.g. for a large number of containers. However, such a sampling plan may pose a considerable risk of accepting defect goods when sampling a small number of containers, for example.
A documented justification is expected for all sampling plans.
Strictly speaking, these requirements only apply for der Canadian market, they can, however, be viewed as state of the art worldwide.
The question with its complete answer can be found in section “Raw Material Testing – C.02.009 & C.02.010” under Q7 – see
“Good Manufacturing Practices (GMP) Questions and Answers / Is the sampling plan based on the (√n+1) acceptable for identifying the number of containers of raw material to be sampled?“
◆ FDA opens Docket on Continuous Manufacturing (17-Apr-18 ECA)
In June 2017, the FDA opened a docket intended for public comments on the topic of continuous manufacturing. A docket is the central system of the U.S. authorities to obtain feedback on new laws, regulations and guidelines. Every comment disclosed there is publicly available. In this special case, the FDA’s main interest concerns the document published by the C-SOPS working group. This document contains definitions and recommendations on continuous manufacturing. It was already published in 2016, but nearly missed in Europe. C-SOPS is short for Center for Structured Organic Particulate Systems. It was founded by a working group of university and industry representatives and is headquartered at Rutgers University.
Up to now, the document is rather a collection of definitions and explanations than a guideline, but it is certainly worth reading. It deals with the production of solid dosage forms (OSD). It explains control strategies for the process as well as the topics of steady state, state of control and mean residence time. These terms play a key role in continuous processes. In addition, it demonstrates the major differences between discontinuous and continuous production and also treats the important issue of batch definition in continuous processes. The number of possible batch definitions in continuous processes is even bigger than in conventional batch production. For instance, a batch can be:
During the release of continuously manufactured products, acceptance criteria such as compliance with CQAs (critical quality attributes) play the same role as in conventional production. It is crucial to ensure batch homogeneity here. It is pointed out that with continuous processes, not only is it possible to sample the final product, but there are many more ways to verify homogeneity and content uniformity, e.g. by analysing data from in-process monitoring and by using spectroscopic methods.
According to the document, it should further be possible to use different sampling methods depending on process knowledge. This is in accordance with the FDA multi-stage validation procedure which reflects that process knowledge increases over time: stage 1 (process design), stage 2 (process qualification) and stage 3 (continued process verification). In continuous processes, real-time-release will become tangible through the use of PAT. It is pointed out that not all IPCs must be part of a real-time-release.
Regulatory and approval issues are addressed as well. The procedures for IND and NDA submissions for instance are briefly discussed. Regarding the latter, the requirements for batch and continuous processes are the same. Post-approval changes are also discussed. Because it is assumed that continuous processes were developed based on the principles of QbD and on those of ICH Q8 (R2), Q9 and Q10, changes should be fairly easy. In further chapters, the topic of changing from a batch to a continuous process is addressed, both for approved products and for those still in the development phase.
Apart from comments on the C-SOPS document described above, the FDA is generally interested in comments and input on the issue of continuous manufacturing.
Please also see the FDA docket “Submission of Proposed Recommendations for Industry on Developing Continuous Manufacturing of Solid Dosage Drug Products in Pharmaceutical Manufacturing“.
◆ New FDA Guidance on Liposomes (01-Jun-18 ECA)
The U.S. Food and Drug Administration, FDA, published its final guidance for industry on liposome drug products in April 2018. It finalizes the revised draft guidance for industry Liposome Drug Products, Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation that has been published in October 2015.
According to the guidance “Liposomes are vesicles composed of a bilayer (uni-lamellar) and/or a concentric series of multiple bilayers (multi-lamellar) separated by aqueous compartments formed by amphipathic molecules such as phospholipids that enclose a central aqueous compartment. In a liposome drug product, the drug substance is generally contained in liposomes.“
Liposome drug products exist as injectable liposome drug products (for example long acting injections). For those, sterility and the absence of pyrogens or bacterial endotoxins has to be shown. Furthermore they occur in form of topical products /cosmetics and oral products (e.g. as a carrier of dietary and nutritional supplements). The use of liposomes is primarily directed at targeted drug delivery. In case of topical application, for example, they release both lipophilic and hydrophilic active substances specifically into the epidermis.
Liposome formulations are different from
The new guidance discusses what types of information should be submitted to FDA in new drug applications (NDAs) or abbreviated new drug applications (ANDAs). It does not cover recommendations specific to liposome drug products to be marketed under biologics license applications (BLAs). However, many scientific principles described in this guidance may also apply to these products. The provided recommendations focus on the unique technical aspects of liposome drug products. The document addresses the following topics:
The guidance refers to Quality by Design (QbD) principles according to ICH Q8(R2) Pharmaceutical Development including screening of critical variables (Critical Quality Attributes, CQAs) and establishment of a Design Space. The inclusion of a detailed process flow diagram and a description of unit operations with ranges for the process parameters and process controls is recommended. The ranges should be supported by pharmaceutical development studies. Liposome drug products are sensitive to changes in the manufacturing conditions, including changes in scale (batch sizes). Appropriate process controls should be established during product development. Some examples of manufacturing process parameters that may affect liposome drug performance are shear force, pressure, pH, temperature, batch-size-related hold times, lyophilization parameters, sterilizing filtration, etc.
Postapproval Changes in Manufacturing (see also ICH Q12 draft)
According to FDA, “liposome drug products are complex and sensitive formulations and response to CMC changes is less predictable than with more conventional formulations. Therefore, changes to the formulation, container closure, site of manufacture, or manufacturing process (including substantive equipment and scale changes) will usually require a prior approval supplement.” FDA emphasizes to contact the appropriate review division associated with the application to discuss questions regarding the type of information to generate or the appropriate reporting mechanism for a postapproval change.
For more Information please see FDA´s Guidance for Industry: Liposome Drug Products, Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation.
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