【讨论】FDA关于混粉取样的进展问答

清歌一曲月如霜

15. FDA recently announced the withdrawal of its draft guidance for industry on Powder Blends and Finished Dosage Units — Stratified In-Process Dosage Unit Sampling and Assessment. What were the Agency’s major concerns with this guidance?

FDA’s major concern was that Sections V and VII of the withdrawn draft guidance no longer represented the Agency’s current thinking, as explained below.

Section V (Exhibit/Validation Batch Powder Mix Homogeneity) recommended that at least three replicate samples be taken from at least ten locations in the powder blender, but that only one of the three replicates be evaluated to assess powder blend uniformity. The Agency currently recommends that all replicate samples taken from various locations in the blender be evaluated to perform a statistically valid analysis. This analysis can demonstrate that variability attributable to sample location is not significant and that the powder blend is homogenous. Statistical tools are available to ascertain both the number of replicates and the number of sampling locations across the blender that should be analyzed to conduct a valid analysis.

Section VII (Routine Manufacturing Batch Testing Methods) acceptance criteria designated to the Standard Criteria Method and the Marginal Criteria Method were based upon the limits published in the United States Pharmacopeia (USP) General Chapter <905> Uniformity of Dosage Units. However, the procedures and acceptance criteria in USP <905> are not a statistical sampling plan and so the results of the procedures should not be extrapolated to larger populations. Therefore, because the procedure and acceptance criteria prescribed in section VII provided only limited statistical assurance that batches of drug products met appropriate specifications and statistical quality control criteria, FDA no longer supports their use for batch release. Currently, there are several standard statistical practices (see references) that, if used correctly, can help to ensure compliance with the current good manufacturing practice (CGMP) regulations, including 21 CFR 211.110 Sampling and testing of in-process materials and drug products, 21 CFR 211.160 General Requirements [Subpart I, Laboratory Controls],and 21 CFR 211.165 Testing and release [of the finished drug product] for distribution.1

References:
1.FDA CGMP regulations: 21 CFR 211.110; 211.160; 211.165. Available at:http://www.accessdata.fda.gov/sc ... rch.cfm?CFRPart=211


Contact for further information:

Karthik Iyer, Consumer Safety Officer
CDER/OC/OMPQ/RSIPT
Karthik.Iyer@fda.hhs.gov

CDER/OC Office of Manufacturing and Product Quality: CGMP Subject Matter Contacts
http://www.fda.gov/AboutFDA/Cent ... /CDER/ucm096102.htm
Date: 8/6/2013

清歌一曲月如霜

16. Why is FDA concerned about proper sampling of powder blends?

The CGMPs require that all sampling plans be scientifically sound and representative of the batch under test (see 211.160(b)). Further, in-process testing of powder blends to demonstrate adequacy of mixing is a CGMP requirement (21 CFR 211.110). Between- and within-location variability in the powder blend is a critical component of finished product quality and therefore should be evaluated. Drug product manufacturers need to use a science- and risk-based sampling approach to assure (a) adequacy of blend mixing and (b) that sampling of the blend is done at a suitable juncture in the manufacturing process. The sampling and analysis needs to ensure that no differences exist between locations in a blend that could adversely affect finished product quality. Traditional sampling using a powder-thief may have drawbacks and limitations, such as causing disturbance to the powder bed, powder segregation, or other sampling errors. However, powder-thief sampling remains widely used and provides reliable results in many cases. The Agency encourages firms to adopt more innovative approaches to ensuring adequacy of mixing (see, e.g., the PAT guidance). If a manufacturer proposes to use a thief sampling method, the reliability of the method should be evaluated as part of analytical methods development.

Contact for further information:

Karthik Iyer, Consumer Safety Officer
CDER/OC/OMPQ/RSIPT
Karthik.Iyer@fda.hhs.gov

CDER/OC Office of Manufacturing and Product Quality: CGMP Subject Matter Contacts

http://www.fda.gov/AboutFDA/Cent ... /CDER/ucm096102.htm

Date: 8/6/2013

清歌一曲月如霜

17. What are some recommended innovative approaches to ensuring adequacy of mixing of powder blends?

Innovative approaches to consider include, but are not limited to: (a) Process Analytical Technology (PAT) real-time monitoring and feedforward controlling of the powder blending process1 and (b) use of Statistical Process Control (SPC) tools to monitor the powder blending process and to maintain a state of control.

When a manufacturer decides to implement PAT or other process-monitoring and control techniques for powder blend homogeneity assessment, its decision should be supported with appropriate data and rationale using a science- and risk-based approach. For example, the effective sample size of powder examined by PAT probes has to be estimated, such that the scale of scrutiny of the PAT powder blending monitoring can be justified.2 The number of PAT probes and their locations also have to be justified. If a scientifically sound PAT monitoring and control strategy is established, it can facilitate the assessment of: (a) variability across locations within the powder bed,3 (b) the variability over time of one location, and (c) the potential correlation between the powder sample and the unit dosage form.

References:

1.FDA Guidance for Industry: PAT - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. September 2004. Available at: http://www.fda.gov/downloads/Dru ... ances/UCM070305.pdf
2.Wu, H.; Tawakkul, M.; White, M.; Khan, M. Quality-by-Design (QbD): An Integrated Multivariate Approach for the Component Quantification in Powder Blends. International Journal of Pharmaceutics, vol. 372 issue 1-2 May 8, 2009. p. 39-48.
3.El-Hagrasy, A.; Morris, H.; D’Amico, F; et al. Near-infrared Spectroscopy and Imaging for the Monitoring of Powder Blend Homogeneity.Journal of Pharmaceutical Sciences, vol. 90 issue 9, September 2001. p. 1298 – 1307.


Contact for further information:

Karthik Iyer, Consumer Safety Officer
CDER/OC/OMPQ/RSIPT
Karthik.Iyer@fda.hhs.gov

CDER/OC Office of Manufacturing and Product Quality: CGMP Subject Matter Contacts
http://www.fda.gov/AboutFDA/Cent ... /CDER/ucm096102.htm

Date: 8/6/2013

清歌一曲月如霜

18. What are the Agency’s recommendations regarding in-process stratified sampling of finished dosage units?

Stratified sampling is recommended to be used when the population is known to have several subdivisions (i.e., locations) which may give different results for the quality characteristics measured. The Agency expects that no significant differences should exist between in-process locations that could affect finished product quality. Between- and within- location variability is a critical component of finished product quality and therefore should be evaluated. Please refer to ASTM E27096 and ASTM E28107 for further guidance on establishing acceptance criteria for a stratified sampling plan.

References

1. ASTM E2709: Standard Practice for Demonstrating Capability to Comply with an Acceptance Procedure.
1.ASTM E2810: Standard Practice for Demonstrating Capability to Comply with the Test for Uniformity of Dosage Units.


Contact for further information:

Karthik Iyer, Consumer Safety Officer
CDER/OC/OMPQ/RSIPT
Karthik.Iyer@fda.hhs.gov

CDER/OC Office of Manufacturing and Product Quality: CGMP Subject Matter Contacts

http://www.fda.gov/AboutFDA/Cent ... /CDER/ucm096102.htm

Date: 8/6/2013

爱雨山

这是国外的论坛吗？

REC

我竟然还能看懂第一行

yanzhengren

谢谢分享。