Sampling in process validation
3 likes4,254 views
This document summarizes guidelines for ensuring blend uniformity in pharmaceutical powder blending. It discusses the types of blending equipment and factors that can influence blend quality. The FDA has issued guidance on assessing blend uniformity, including withdrawn 1999 draft guidance. Industry groups like PDA have also published technical reports on validation methods. Modern techniques like near infrared spectroscopy can provide real-time, non-invasive analysis to help ensure blend uniformity and reduce sampling errors in quality testing.
Sampling in process validation
- 1. 46 Journal of GXP Compliance A Guide to Blend Uniformity By Trudy Yin OVERVIEW OF BLENDING PROCESS AND EQUIPMENT The process of blending is commonly defined in the pharmaceutical industry as: the mixing of various bulk powder ingredients (e.g., drugs, excipients), targeted for a homogeneity and uniform distribution of the mixture. Each pharmaceutical product has its unique blend of raw materials; therefore, a careful selection of manufac- turing process equipment and methods is inevitable. The quality of the resulting blend depends highly on the types of blenders or mixers used; the “flowability” (flow behavior) of powder during the blend cycle is factored into the finished product quality. The mechanics of blending, which involves the principles of shear, convec- tion, and diffusion (or dispersion), is achieved by the use of industrial blenders or mixers. The equipment employed to accomplish the process of blending can be categorized as either rotating or fixed shell blenders. Rotating shell blenders (i.e., drum, cross-flow, double cone, and twin-shell) accomplish the mixing process by rotating the blender shell around a fixed axis and by relying upon a sliding or rolling motion of the powder. To aid in this mixing process, many systems will utilize internal baffles. Fixed shell blenders (i.e., ribbon, screw, and impeller mixers), on the other hand, rotate internal blender parts, such as an impeller or paddle, and pro- duce a continuous cutting and shuffling motion. Shear- ing force that breaks apart large conglomerates of pow- der is, therefore, developed by this kind of cutting and shuffling motion. Pony, planetary, and high shear mixers are commonly used in conjunction with blenders. There are a number of process and product vari- ables and characteristics that influence the quality of ABSTRACT The powder blending process has been historically identified as a challenging operation in Oral Solid Dosage (OSD) form manufacturing. Insufficient blending results in poor active ingredient mixing with excipients. Excessive blending could adversely impact the distribution of drug content (content uniformity) in the final product. Companies suffer financial setbacks due to rework of poor quality product, and more severely, legal action being taken because of non-compliance. With harmonizing efforts, government agencies, such as the U.S. Food and Drug Administration (FDA), join with industry experts and scientists to develop corresponding principles and guidelines in order to assist drug manufacturers. According to the FDA's current Good Manufacturing Practice (cGMP) Code of Federal Regulations (CFR), Title 21, Part 211-Current Good Manufacturing Practice for Finished Pharmaceuticals standard; particularly section 211.110, Sampling and testing of in-process materials and drug products of Subpart F states, written procedures shall be established and followed for “adequacy of mixing to assure uniformity and homogeneity…” In the following blend uniformity discussion, we will examine this rule and demonstrate how guidelines emerge, how they are interpreted, and their practical adoption to current industrial methodologies and/or technologies.
- 2. 47October 2007 • Volume 12, Number 1 Trudy Yin mixing and its final blend. Incorrect process parame- ters, for instance, when discharging the powder with improper flow rate could create over-flooding or unsteady flow issues, ultimately affecting the final blend uniformity. Inadequate mixing time and speed could also result in poorly blended mixture, clump for- mation, and segregation. Product characteristics include particle size, density, morphology, shape, etc., of the powder ingredients. Large coarse particles with higher molecular weight will, for example, settle to the bottom of the blender vessel; whereas the smaller finer particles will rise to the top. Particle density affects the sedimentation or floating ability, for which uniform dis- tribution of the powder mixture could be warranted. Shape, stickiness, and electrostatic charge of the parti- cles may also resist or mark negative impact on the Category Sub-Category Physical Characteristics of the Ingredients Actives • Particle Size • Density • Morphology • Shape • Amount Excipients • Particle Size • Density • Morphology • Shape • Amount Chemical Compositions of the Ingredients Actives • Compatibility with excipients • Adhesiveness • Electrostatic charges • Impurities • Degradation profile Excipients • Compatibility with actives • Adhesiveness • Electrostatic charges Blending Equipment Rotating Shell Blenders • Drum • Cross-flow • Double Cone • Twin-shell Fixed Shell Blenders • Ribbon • Screw Blending Methods Rotating Shell Blenders • Rotating the blender shell around a fixed axis. Fixed Shell Blenders • Rotating internal blender parts, such as an impeller or paddle, and producing a continuous cutting and shuffling motion Process Parameters • Mixing Time • Mixing Speed • Flow Rate • Volume Factors Influencing the Quality of the Blend (Source: PAREXEL Consulting) Factor Figure 1 Blend Quality Factors
- 3. 48 Journal of GXP Compliance Trudy Yin mixing process. Caution should be taken throughout product and process development in order to eliminate or minimize variability. Figure 1 summarizes some major factors which contribute to the analysis and determination of the degree of confidence in these quality attributes, namely, the homogeneity and uni- form distribution of the final blend mixture. Scientifically valid procedures, appropriate test methods, and in-process controls and limits should be established in the developmental phase to evalu- ate the adequacy and effectiveness of such blending process as well as to ensure uniformity and homo- geneity of the final blend product. The greatest chal- lenge confronting oral solid dosage form manufactur- ers today is the difficulty they encounter in applying sound methods and rationales to the blending opera- tion and validation, respectively. FDA GUIDANCE FOR INDUSTRY FDA announced the availability of a draft guidance for industry entitled “ANDAs: Blend Uniformity Analysis,” on August 27, 1999 (64 FR 46917) that was with- drawn on May17, 2002, after comments from the public raised scientific issues relating to the scope and methodology of the blend uniformity draft guide- line.1,8 This draft guidance was intended to provide recommendations to abbreviated new drug applica- tion (ANDAs) filings based on 21 CFR 314, not on cGMP regulations. In other words, it guided industry to what information should be provided in an ANDA in order to demonstrate bioequivalence and to estab- lish in-process acceptance criteria related to blend uniformity analysis (BUA). After careful consideration of the written comments submitted, FDA decided to withdraw the draft guidance due to (1) adequacy of current blend sampling techniques and (2) appropri- ateness of various test methods for assessing blend uniformity.1 Although this draft document has never been implemented, and the 21 CFR 211.110 does not require BUA, an applicant or manufacturer must still comply with any predicate rules and applicable regulations to ensure the identity, strength, quality, purity, and bioavailability of the drug product (21 CFR 314.50(d) (1) (ii) (a)).1 A manufacturer must also monitor and validate the performance of processes that could be responsible for variability, including ade- quacy of mixing to ensure uniformity and homogene- ity (21 CFR 211.110(a) (3)).1 An evaluation of unifor- mity and/or equivalent testing may be necessary to fulfill cGMP requirements. Issued on October 2003, new draft guidance, “Powder Blends and Finished Dosage Units- Strati- fied In-Process Dosage Unit Sampling and Assess- ment,” was made available and distributed to solicit public comments and suggestions. “Stratified Sam- pling” is defined in this new guidance and the sam- pling method, data evaluation, as well as analysis are further discussed in this guidance.2,3 However, the guidance states that the methods described are not intended to be the only methods for meeting agency requirements for the demonstration of the adequacy of powder mix. Traditional powder blend sampling/testing, finished product content uniformity (CU) testing or alternate approaches may also be used to satisfy cGMP requirements. The finalized guidance represents the agency's current thinking on “Powder Blends and Finished Dosage Units-Stratified In-Process Dosage Unit Sampling and Assessment.” Manufacturers are not encouraged to blindly follow, but evaluate the methods, criteria, and recommenda- tions, presented in this new guidance for appropriate- ness before implementation. PDA TECHNICAL REPORT NO. 25 In 1997, the International Association for Pharmaceu- tical Science and Technology (PDA) issued Technical Report No. 25, “Blend Uniformity Analysis: Validation and In-Process Testing,” to provide scientifically sound methods for the appropriate evaluation of blending processes. The intent of this technical report was to establish statistically derived methods (e.g., Bergum's method) and criteria to overcome the impact of sampling errors. The report represented the views of authors, industry experts, and PDA's Solid Dosage Process Validation Committee. The FDA's review of the draft of this report resulted in a letter response from FDA's Center for Drug Evaluation and Research (CDER) office dated August 29, 1997, in
- 4. 49October 2007 • Volume 12, Number 1 Trudy Yin which FDA commented and questioned the rationale behind the statistical approach advocated in the report.4 PDA documented its response to FDA in a letter dated October 9, 1997.3,4 Later, in regard to the agency's Docket No. 99D-2635, “Draft Guidance for Industry, ANDA's Blend Uniformity Analysis” of 1999, PDA was given the opportunity to comment on the proposed draft guidance, and suggestions were doc- umented in a letter dated October 26, 1999. A subse- quent workshop and meeting with the working group (BUWG) were also conducted in 2000 and a draft recommendation of the use of stratified sampling of blend and dosage units to demonstrate adequacy of mix for powder blends was issued for peer review and then published in the PDA Journal of Pharma- ceutical Science and Technology.3 This brief history of guideline development demonstrates how consen- sus is reached between FDA and the public. Informa- tion on Technical Report No. 25 has also been cross- referenced and incorporated into the FDA 2003 draft guidance: “Powder Blends and Finished Dosage Units- Stratified In-Process Dosage Unit Sampling and Assessment.” SAMPLING AND ASSESSMENT In order to adequately measure between and within- location variability, the most appropriate blend sam- pling techniques and procedures should be devel- oped and chosen. Blend sample analysis should be conducted on both the blend and intermediate bulk containers (IBCs) to identify the range of blending times, dead spots in blenders, segregation in IBCs, and the possibility of sampling errors, etc. Stratified sampling is defined in the FDA draft guidance, “Pow- der Blends and Finished Dosage Units- Stratified In- Process Dosage Unit Sampling and Assessment” as: “the process of collecting a representative sample by selecting units deliberately from various identified locations within a lot or batch, or from various phases or periods of a process to obtain a sample dosage unit that specifically targets loca- tions throughout the compression/filling operations that have a higher risk of pro- ducing failing results in the finished prod- uct uniformity of content.” 3 A stratified sampling technique is used to collect in- process dosage units throughout the compression/fill- ing process. It can be used, therefore, as an alterna- tive to routine blend sample analysis. Establishing a sample size is important for the analysis of blend samples. The FDA Draft Guidance document stated that the blend sample size should be 1 to 3 dosage units. The Blend Uniformity Working Group (BUWG) from Product Quality Research Institute (PQRI) pro- posed that sample quantities larger than 3X be allowed if they could be scientifically justified. The demonstration of content uniformity of the final pow- der blends cannot be absolutely absent of sampling bias and errors. Physical design of the thief, physical and chemical properties of the formulation, and sampling technique are major factors that can affect sampling errors.4 Since sampling errors make it a big challenge to validate the blending operation, blend sample data should be used in conjunction with in- process dosage unit data. Assessment and validation (i.e., exhibit and process validation batches) should optimally be per- formed separately on the uniformity of the powder blend, the in-process dosage units, and on the fin- ished product. The FDA has proposed the following acceptance criteria3: 1. Assay one sample (n) per location, n≥10 2. RSD of all individual results ≤5.0% 3. All individual results within 10.0% of the mean Only after an initial assessment/validation is com- pleted, routine manufacturing controls and criteria shall follow. All these cGMP process controls and product testing are necessary to ensure batch homo- geneity and batch-to-batch reproducibility. Procedures will be written for material handling, machine opera- tions, cleaning, maintenance, as well as sample col- lection, and analysis as minimal. In analysis of batch normality, the FDA has proposed results to be classi- fied as readily or marginally pass. Readily pass homogeneity shall meet the following criteria3:
- 5. 50 Journal of GXP Compliance Trudy Yin 1. RSD ≤ 4.0%, for each batch n≥ 60 2. Each location mean within 90.0%-110.0% of target strength 3. All individual results within 75.0%-125.0% of target strength Marginally pass homogeneity shall meet the following criteria3: 1. RSD ≤ 6.0%, for one batch n≥ 140 2. Each location mean within 90.0%-110.0% of target strength 3. All individual results within 75.0%-125.0% of target strength Passing the readily pass criteria for all validation and exhibit batches qualifies a product to use standard test- ing during routine manufacture. Otherwise, tightened testing must be used for products that marginally pass during validation. If test results fail readily pass, remain- ing dosage units shall be tested and compared with marginally pass criteria. If tested samples again fail marginally pass criteria, the company shall investigate, make corrections, remix and reassess the blend and the product accordingly. Standard and tightened tests for routine verification of manufacturing batches are described as per FDA draft guidance: “Powder Blends and Finished Dosage Units- Stratified In-Process Dosage Unit Sampling and Assessment.” Evaluation can be done in the two proposed methods: Standard Criteria Method (SCM) and the Marginal Criteria Method (MCM); commensurate with the compendial procedure described in the USP. Likewise, the PDA Technical Report No. 25 introduces the conception of a holistic approach whereby the mean and variances of the blend are compared with those in the finished prod- uct. In the report, it simply states that “the overall mea- surement of the effectiveness of the blending and the extent of post blending particle segregation are obtained by a thorough evaluation of the blend and the product.” To evaluate product uniformity, detailed statisti- cal methods, such as standard deviation prediction, Bergum's method, variance component analysis, etc., are recommended for validation purposes. MODERN TECHNOLOGIES ON ANALYTICAL METHOD Near-InfraRed Spectroscopy (NIRS) and other imag- ing techniques have drawn much attention in the chemical industry over the past decade. NIRS is a noninvasive on-line monitoring system with measure- ments based on the standard deviation of the spectra obtained.5-8 Because the conventional method of in- process thief sample collection, laboratory testing, and verification is considered labor intensive for many manufacturers and results are irreproducible often times, this type of process analytical technology (PAT) offers a solution while providing “real-time” in- process control without having to collect samples.6 Information provided by NIRS chemical imaging from different time points throughout the blending cycle, can be analyzed statistically to permit quantitative evaluations of the blend content uniformity. Prediction of product performance is more reliable using the pattern recognition tools on the NIR spec- trums to the identification and characterization of the materials being tested. The disadvantage of tradi- tional equipment such as the error prone manual sample thief can be eliminated; and therefore, reduces sampling bias and errors. With the continu- ous efforts of new development and emerging tech- nologies, a more thorough (i.e., API plus excipients) and higher analytical accuracy with improved produc- tion efficiency is just around the corner.6-8 REFERENCES 1. http://www.fda.gov/OHRMS/DOCKETS/98fr/051702a.htm, ANDAs: Blend Uniformity Analysis; Withdrawal of Draft Guidance, as of 10/22/06. 2. http://a257.g.akamaitech.net/7/257/2422/14mar20010800/ edocket.access.gpo.gov/2003/03-28045.htm, Draft Guid- ance for Industry on Powder Blends and Finished Dosage Units-Stratified In-Process Dosage Unit Sampling and Assessment; Availability, as of 10/22/06. 3. www.fda.gov/cder/guidance/5831dft.pdf, Guidance for Industry Powder Blends and Finished Dosage Units- Stratified In-Process Dosage Unit Sampling and Assess- ment, as of 10/22/06.
- 6. 51October 2007 • Volume 12, Number 1 Trudy Yin 4. Berman, J, Ph.D., Elinski, D.E., Gonzales, C.R., Hofer, J.D., Jimenez, P.J. Ph.D., Planchard, J.A., Ph.D., Tlachac, R.J., Vogel, P.F., 1997, “Blend Uniformity Analysis: Validation and In-Process Testing,” Technical Report No. 25. PDA 51:S1- S99. 5. http://www.fda.gov/ohrms/dockets/ac/01/slides/ 3763s1_14_hussain/tsld001.htm, Optimal Applications of “In-Line” or “At-Line” Manufacturing Controls in Pharmaceuti- cal Production, as of 11/24/06. 6. Sullivan, M., 2006, “The Use of NIR as a PAT Tool for Measuring Blend Uniformity,” SPECTROSCOPY SUPPLE- MENT: Process Analytical Technologies, AN ADVANSTAR PUBLICATION, U.S.A. 7. El-Hagrasy, A.S., Morris, H.R., D'Amico, F., Lodder, R.A., Drennen III, J.K., 2001, “Near-Infrared Spectroscopy and Imaging for the Monitoring of Powder Blend Homogeneity,” Journal of Pharmaceutical Sciences, Vol. 90, No. 9: 1298- 1307. 8. Popo, M., Romera-Torres, S., Conde, C., and Romanach, R.J., 2002, “Blend Uniformity Analysis Using Stream Sam- pling and Near Infrared Spectroscopy,” AAPS Pharm- SciTech, article 24. ABOUT THE AUTHOR Trudy Yin is a consultant with PAREXEL Consulting, a business unit of PAREXEL International and a leading global life sciences consultancy serving the bio/phar- maceutical and medical device industries. Ms. Yin pro- vides strategic compliance and operational perfor- mance excellence services to clients. Her expertise includes design, qualification, and implementation of guidelines that are regulatory compliant. Ms. Yin holds a B.S. degree in Biological Sciences from University of California, Irvine. She is a Quality Systems regula- tion Certified Compliance Professional from the Cen- ter for Professional Innovation & Education (CfPIE) and a senior member of the International Society for Pharmaceutical Engineering (ISPE) and the American Society for Quality (ASQ). You can contact Ms. Yin at Trudy.Yin@PAREXEL.com. Article Acronym Listing ANDA Amended New Drug Application API Active Pharmaceutical Ingredient BUA Blend Uniformity Analysis BUWG Blend Uniformity Working Group CDER Center for Drug Evaluation and Research CFR Code of Federal Regulations cGMP Current Good Manufacturing Practice CU Content Uniformity FDA Food and Drug Administration IBC Intermediate Bulk Container MCM Marginal Criteria Method NIRS Near Infrared Spectroscopy OSD Oral Solid Dosage PAT Process Analytical Technology PQRI Product Quality Research Institute SCM Standard Criteria Method