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FDA reviewers aim to assist ANDA sponsors in building quality into their submissions by clarifying components of the applications. Part 4 addresses manufacture and container closure.
As part of FDA's Office of Generic Drugs' (OGD) ongoing effort to streamline the review process and reduce the number of deficiencies cited for abbreviated new drug applications (ANDAs), a series of articles is being published to provide transparency and clarity to applicants submitting applications in the question-based review (QbR) format. The articles highlight the need and significance of science-based justification in establishing drug substance (DS) and drug product (DP) specifications, in-process controls, choice of formulation, selection of a product design, and selection of the manufacturing processes. Part 1 of this series, which dealt with the deficiencies cited in the drug substance section, was published in January 2010 (1). Part 2 of the series regarding drug product composition and excipients and Part 3, regarding the control of the drug product and stability, were published in August 2010 (2) and February 2011 (3), respectively.
The current article is the last of this series, with the focus on providing clarification regarding some common deficiencies cited in the drug product manufacturing (3.2.P.3) and the container closure system (3.2.P.7) portions of ANDA submissions using the Common Technical Document (CTD) and Question-based Review–Quality Overall Summary (QbR-QOS) format as a guide. See the sidebar for a list of some of the deficiencies and comments related to these sections. This is not an all-inclusive list of comments and deficiencies pertaining to the drug product manufacturing and container closure controls and information; but includes some questions that are cited frequently.
There are a myriad of manufacturing processes related to dosage forms available in the market. It is beyond the realm of this article to cover all this information. Thus, the focus will be chiefly on the deficiencies and other comments raised while reviewing the in-process data and controls. In-process controls (IPCs) and manufacturing data for the exhibit batches represent sections of ANDA submissions where a majority of manufacturing deficiencies are cited.
Examples of Commonly Cited Manufacturing (3.2.P.3) and Container Closure System (3.2.P.7) Deficiencies and Comments*
Before delving into IPCs, we would be remiss without noting a common deficiency with regard to proposed batch formula. A deficiency is often cited when the information regarding the actual manufacturing formula for the exhibit lot and the proposed commercial lots is not provided. It is preferable that the quantities of all the raw materials used in the formulation including those, which do not appear in the final formulation, be provided in a clear tabular format for ease of comparison. Any overages should be indicated clearly and justified. Overages and their acceptability have been discussed in detail in Part 2 of this series (2).
In-process controls and results
Generally speaking, there are several areas in the manufacturing section related to in-process controls and exhibit batch results that raise questions during the review of an ANDA. These areas can be broken down further into the following general categories: reconciliation, in-process tests, and the manufacturing process.
Reconciliation.An issue that is often unaddressed in the ANDAs is unjustified, low reconciliation of the exhibit lots. In the QbR–QOS, as well as, the body of data, a table for reconciliation should be provided. Yield should be cumulative and all losses accounted for with adequate rationale for the losses. Applicants are routinely asked to demonstrate how the low reconciliation observed in the exhibit batches will be corrected or mitigated for the commercial process. ANDA applicants are encouraged to include a reference to any applicable investigation of losses to avoid deficiencies cited on this topic.
In-process tests. Often, a clear description of the stages of manufacturing at which the sampling is performed for in-process controls is requested. On many occasions, ANDA applicants do not provide this information either in the QbR–QOS, or the Section 3.2.P.3.4, but reference the executed and the proposed commercial batch records, instead. To facilitate the review of the ANDA, this information should be provided and the QbR FAQ document provides additional guidance on this point (4).
Also, the frequency of testing during compression or other similar processes should be proposed and justified based on batch size and equipment used. Additionally, when changes are made to the release or regulatory/shelf-life specifications for the drug product, the applicant should assess the impact on the proposed in-process controls and revise them accordingly (e.g., disintegration, dissolution, residual solvents, etc.). In general the in-process controls should not be more relaxed than the drug product release criteria.
A frequently asked question for solid oral dosage forms is regarding adequate in-process control of the blend, based on the acceptance criteria for the assay of the drug product. This is especially common when the release assay criterion for the drug product is tighter than the commonly proposed range of 90.0–110.0% of the labeled amount. In these cases, a composite blend assay with proposed range comparable to that of assay of the drug product during routine release analysis is desirable.
For parenterals, deficiencies are often cited regarding adequate or excess fill volume. Usually, containers for parenterals are filled with volumes in slight excess of the labeled amount that is to be withdrawn. The excess volume is meant to be sufficient to permit withdrawal and administration of the labeled amount. It is recommended that the US Pharmacopeial Convention's USP <1> and <1151> should be followed for excess volume (5). However, excess volume may be justified at lower than recommended in USP <1151>. This may be justified based on data, on multiple containers, demonstrating that the intended volume can be extracted consistently or by inclusion of a routine extractable volume test. Large overfills, exceeding USP <1151>, should also be appropriately justified as this excess may pose a potential safety concern.
Manufacturing process.For manufacturing processes which involve dry blending, the ANDA applicant is frequently questioned regarding the possibility of powder segregation. It is well known that achieving and maintaining homogeneous blends of powders are critical for establishing the quality of the solid pharmaceutical dosage forms, especially in formulations involving small amounts of highly potent components. In most cases, the individual components of the blend are powders with differing physical characteristics such as particle size distribution, density, shape, and cohesiveness. These materials may demonstrate tendency to segregate and lead to lack of homogeneity of the final blend. Thus, it is desirable that the ANDA applicant demonstrate a thorough understanding of the blending process and possibility of powder segregation in the pharmaceutical development section, 3.2.P.2. Additional controls for a blend may include, but should not be limited to, particle size distribution of the various components of the blend, particle size distribution of the final blend, flow characteristics and density.
The justification of the proposed tablet compression controls (usually the hardness range) is often requested from the ANDA applicant. The proposed range of hardness during compression and during release or stability testing, should to be justified by demonstrating that the drug product meets the dissolution and the friability criteria at the lowest and the highest points of the proposed ranges. However, the ANDA applicant may refer to studies performed during pharmaceutical development as justification for the proposed range.
When an applicant uses a wet granulation process, it is preferred that a quantitative end point determination is proposed. As factors such a solvent addition and granulation time may be critical to producing consistent, high quality product process, adequate controls should be in place. In many cases, a deficiency is cited if no control or justification is provided by the applicant and the sole control proposed is a subjective, visual observation. For high shear processes, suitable controls may be related to the change in power consumption with respect to the granulation equipment (e.g. amperage). For fluid bed processes, moisture content can be a suitable control for end point of the desired granules. The applicant may also choose to justify the proposed processing ranges of solvent addition, granulation time, etc., during pharmaceutical development studies.
Other issues that arise during review of ANDA submissions, with respect to use of wet granulation processes, are controls for the granulation solvent used. If organic solvents are used in the granulation, appropriate controls should be proposed during the process and/or in the drug product release specification. The following of the recommendations found in USP <467> and OGD Q&A documents may ensure that the residual solvents are adequately identified controlled (5, 6). If water is used as the granulating solvent, it is recommended that a control for water content be proposed, with rationale for the proposed criterion as a function of impact on the stability and quality of the product. Studies to assess impact of water content on product stability and quality may be performed during pharmaceutical development.
Dosage forms comprising multi-unit beads (pellets) or multi-particulates in capsules are a growing area for ANDA applicants. These dosage forms are convenient as they have the capability of providing optimal release profiles (e.g. some varied combination of immediate, delayed and extended release) for single drugs or drug combinations. An added advantage of these dosage forms are as the possibility of alternative administration techniques for certain populations, such as sprinkling beads (pellets) onto soft food. Since many of the beads (pellets) are manufactured as coated, modified release products in order to retain their integrity during mastication, it has been proposed in a draft guidance from the FDA (7), that the bead size be limited to not more than 2.0 mm. Thus, it is recommended that in-process controls be incorporated which establish the final bead size for these dosage forms. In addition, if the dosage form is comprised of multiple controlled release delivery systems (i.e., immediate, delayed and/or extended release pellets), in-process controls need to put in place at the appropriate manufacturing stages for the beads, which establish and monitor the release profile of the beads.
Finally, deficiencies may be cited in the case of parenterals, and other liquid formulations, when justification is not provided regarding the compatibility of the listed manufacturing equipment process materials and the drug product solution. Again, compatibility of the dosage form with the process materials which come in direct contact with the dosage form during manufacturing is recommended to be a part of pharmaceutical development studies.
These comments only scratch the surface with regard to types of in-process controls and data that are provided in submitted applications. Deficiencies will be cited for these and other manufacturing processes if it is apparent the processes are not well understood; and it is imperative that adequate justification be provided so that the risk of problems occurring during commercialization be minimized.
2.3.P.7 Container Closure System
With respect to the container and closure system (CCS), there are related questions in 2.3.P.2.4 and 2.3.P.7 of the QbR–QOS. Often information in one or both sections are missing or inadequate. There are assumptions made, based on previously approved ANDAs, which lead to ANDA applicants not providing necessary information in their submissions. While it is generally appropriate to reference approved CCS from other ANDA, it may not always be appropriate if specific drug substance or drug product characteristics need to be mitigated by the use of a specific CCS (e.g. moisture protection, light protection, droplet size, use of an inert system, etc.). If a statement is provided referencing products that have been approved using the same packaging system, then a copy of the test results for the components should be provided in the body of data, and in some cases, justification that this previously approved system is appropriate to the specific product based on the existence of similar drug substance or product characteristics.
In the development section (2.3.P.2.4) of the QbR–QOS, the following question is linked to the rationale for choice of the container closure system:
• What specific container closure attributes are necessary to ensure product performance?
Whereas in 2.3.P.7, specific details on the chosen system should be provided to answer this QbR question:
• What container closure system(s) is proposed for packaging and storage of the drug product? Has the container closure system been qualified as safe for use with this dosage form?
In the development section, the rationale for choosing a CCS should be provided. This is an opportunity for the sponsor to discuss any studies conducted to identify any critical attributes including suitability (protection, compatibility, and performance) and safety of the CCS. It is recommended to take into consideration the recommendations and information found in current FDA guidance (8) to decide critically of attributes based on the dosage form.
Suitability for use. Suitability for use includes multiple characteristics of the CCS with respect to performance, functionality, and safety. In too many cases, testing that will be used to ensure CCS performance and safety is not provided or is poorly documented. Relevant compendial test results and controls (e.g., USP <381>, <87>, <88>, <660>, <661>, and <671>) should be also provided, as appropriate (5). These tests are intended to demonstrate CCS identity, performance, suitability, compatibility and safety. If this information is lacking deficiencies will be cited.
Any other testing or certification, such as Code of Federal Regulations (CFR) references to demonstrate suitability of use for pharmaceutical products, should be also provided. (e.g., 21 CFR sections 174–186 provide a list of materials that are safe for use in direct or indirect food contact) (9).
In many cases, for solid oral products, the most crucial container closure development studies are related to drug product chemical stability. Although tablet integrity (physical stability) may need to be studied for low hardness or highly friable tablets such as orally disintegrating tablets (ODTs) or chewable tablets. Further discussion on this topic can be found later in the article.
For any drug products that incorporate delivery devices (e.g. nasal sprays, inhalation products, oral solutions, ophthalmics, etc.), pharmaceutical development studies conducted with respect to demonstration of performance should be discussed. Performance testing of the CCS might include dropper consistency, calibration of delivery device, droplet size, etc. It may also be necessary to compare the ANDA product performance with the reference listed drug (RLD) to demonstrate similar dosing will occur.
Specific cases. In the case of parenteral products, and other drug products that are solutions or suspensions, compatibility testing should be provided (e.g., extractables and leachables for the stoppers or the CCS materials, as applicable, dye or adhesive migration from labeling, etc.). If this information is not provided, deficiencies have and will continue to be cited. Also, the analytical method used for the analysis should be appropriate for the detection of the extractables and leachables from the CCS. While proposing quality or safety limits for the extractables and leachables, it should be remembered that these are not covered by the International Conference on Harmonization (ICH) Q3B (R2) guideline or the related ANDA impurity guidance (10, 11). Thus, the acceptance criteria proposed should be supported by sound rationale, based on available toxicological information in the public domain, or information provided in the applicable CFR sections (9).
In USP <1>, closures for multiple-dose containers permit the withdrawal of the contents without removal or destruction of the closure (5). The closure permits penetration by a needle and, upon withdrawal of the needle, closes at once, protecting the container against contamination. Suitable controls (e.g., coring, seal-sealing, fragmentation, etc.) should be in place to demonstrate that the stopper is adequate if it is intended to be used in a multiple use product.
With respect to blister packages, an often cited deficiency is a lack of data to demonstrate that the blister components protect the product from moisture. We recommend that data be provided for moisture permeation of the proposed blister pack. Additionally, as an in-process, and in some cases for release and stability analysis, a leak test may be necessary.
Occasionally inquiries are made regarding integrity of tablets during transportation and storage. This is common when the dosage form is an ODT or some other low hardness tablet (e.g., chewable tablet), which are packaged in bottles having large headspace. It is well known that tablets are constantly subjected to mechanical shocks and abrasion during the transportation and storage. Such stresses can lead to chipping, abrasion or even breakage of orally disintegrating tablets, which are known to have low friability. It is therefore important for the ANDA applicant to demonstrate that the tablets are able to withstand such stress without damage and provide information to assure the integrity of the tablets during transportation and storage. In use and "shipping" studies should be taken into consideration when designing low hardness products, as well as, other dosage forms that may be affected by transportation.
This concludes our discussion on the commonly cited deficiencies in ANDA submissions. To summarize the entire series, ANDA applicants should endeavor to demonstrate product and process understanding; and provide sound scientific and regulatory justification for all information provided and all controls that are proposed in their applications.
As stated throughout, this series is not intended to be an all-inclusive list of deficiencies cited, but only a survey of what types of information are being requested from ANDA applicants, since the implementation of the QbR-QOS format. Throughout the series, the authors have attempted to provide some rationale for citation of common deficiencies. The phrase "pharmaceutical development" has appeared like a refrain in every section of every article. This underlines the importance of adequate pharmaceutical development studies, performed during the initial development of the drug product, which in turn leads to justification for the chosen materials, formulations and processes; and may reduce the instances of such deficiencies being cited.
1 Numbering in section heads correspond to those in the Common Technical Document (CTD).
The authors wish to acknowledge Keith Webber, PhD, Acting Office Director, OGD; Lawrence Yu, PhD, Deputy Director for Science, OGD; and Vilayat A. Sayeed, PhD, Director of Chemistry Division III, OGD, for their input and encouragement as the authors put together this series of articles. We would also like to thank Devinder S. Gill, PhD, Deputy Director of Chemistry Division III, OGD, for his contributions as co-author of Parts 2 and 3 of this series.
The views and opinions in this article are only those of the authors and do not necessarily reflect the views of policies of FDA.
Aloka Srinivasan, PhD,* is a team leader, and Robert Iser, M.S., is an acting director, both at the Office of Generic Drugs within the Office of Pharmaceutical Science, under the US Food and Drug Administration's Center for Drug Evaluation and Research, Aloka.Srinivasan@fda.hhs.gov.
*To whom all correspondence should be addressed.
1. A. Srinivasan and R. Iser, Pharma. Technol. 34 (1), 50–59, (2010).
2. A. Srinivasan, R. Iser and D. Gill, Pharma. Technol. 34 (8), 45–51 (2010).
3. A. Srinivasan, R. Iser and D. Gill, Pharma. Technol. 35 (2), 58–67 (2011).
4. FDA, QbR Frequently Asked Questions (June 4, 2007).
5. USP 33–NF 28 (US Pharmacopeial Convention, Rockville, MD, 2011).
6. FDA OGD, Residual Solvents in ANDAs: Questions and Answers (Rockville, MD, Oct. 28, 2008), www.fda.gov/downloads/AboutFDA/CentersOffices/CenterforDrugEvaluationandResearch/ucm119607.pdf.
7. FDA, Draft Guidance for Industry: Size of Beads in Drug Products Labeled for Sprinkle (Rockville, MD, January 2011).
8. FDA, Guidance to Industry: Container Closure Systems for Packaging Human Drugs and Biologics (Rockville, MD, May 1999).
9. FDA, "21 CFR 176 Indirect Food Additives: Paper Board and Paperboard Components through 21 CFR 186 Indirect Food Additives Affirmed as Generally recognized as safe (Rockville MD, Apr. 1, 2010).
10. ICH, Q3B, Impurities in New Drug Products (R2) (Geneva, July 2006)
11. FDA, OGD, Guidance for Industry: ANDAs: Impurities in Drug Products ((Rockville, MD, November 2010).
This article represents the views of the authors and not of FDA.