FDA Perspectives: Common Deficiencies in Abbreviated New Drug Applications: Part 2: Description, Composition, and Excipients

As part of the US Food and Drug Administration's Office of Generic Drugs (OGD) ongoing effort to streamline the review process and reduce the number of deficiencies cited for applications, a series of articles are being published to provide transparency and clarity to the sponsors 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 for both DS/DP, 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).

The current article is a continuation of this series, with the focus on providing clarification with respect to intent and criticality of some common deficiencies cited in the description and composition (3.2.P.1) and excipient (3.2.P.4) portions of abbreviated new drug application (ANDA) submissions using the Common Technical Document (CTD) and Question-based Review–Quality Overall Summary (QbR-QOS) format as a guide. Also included are other issues related to section P.1 and P.4. These P.1 and P.4 issues are not part of routine deficiency letters, however are considered critical to the quality of the drug product; if not addressed these may have regulatory as well as quality impact. Please refer to the sidebar, "Examples of commonly cited deficiences and comments." This list is not all-inclusive but does include frequently cited comments and deficiencies pertaining to composition and excipients.

Examples of commonly cited Description, Composition, and Excipient deficiencies and comments*

2.3.P.1 Description and composition of the drug product¹

There are three sets of QbR-QOS questions with respect to composition of the drug product. They are as follows:

1. What are the components and composition of the final product? What is the function of each excipient?

2. Does any excipient exceed the Inactive Ingredients Database (IID or IIG) limit for this route of administration?

3. Do the differences between this formulation and the reference listed drug (RLD) present potential concerns with respect to therapeutic equivalence?

The description and composition information is satisfactory in the majority of ANDAs submitted to OGD. Usually there is no need to issue deficiencies or comments to ANDA sponsors. However, when deficiencies are cited, they typically fall into four main categories. The first category is with respect to issues with the composition information. This information is typically presented in a tabular format in 2.3.P.1 and 3.2.P.1. When deficiencies are provided to sponsors they are, in many cases, related to insufficient clarity in the answers to the first set of QbR-QOS questions noted above. Second, there are common deficiencies cited with respect to proposed overages. The third category is related to the qualitative (Q1) or quantitative (Q2) formulation including the comparison to the reference listed drug (RLD) or the IIG (2). These are related to the second and third QbR-QOS questions above. The final category of composition related deficiencies is related to the make-up of ingredients (e.g., iron oxide in coatings).

Drug product composition information. Very few deficiencies and comments are cited with regard to the information presented in the composition tables. If cited, these include not providing the percent of each excipient (e.g., w/w %) in the formulation. The intent of this question is to clearly provide the reviewer the intended function of the multifunctional excipients in the formulation at the proposed w/w % level. This information is critical to the assessment of the formulation as it is well documented that changing the w/w % of multifunctional excipient in the formulation can potentially change the function. In cases of multistrength products, it also provides the information on the dose proportionality over the range of strengths.

An applicant should provide a list, for each product strength where applicable, the quantitative composition, function of excipient, grade (e.g., Avicel PH 101 etc.), the standard (e.g., US Pharmcopeia, National Formulary, Food Chemicals Codex, etc.), and origin as applicable (e.g., vegetable or animal source) of each component. This list should include all materials that are used throughout the process including organic and aqueous solvents and processing aids used in the manufacturing process and are removed during the process (e.g., water, alcohol, nitrogen, etc.). Information for all ingredients including specifications and certificates of analysis should be provided in 3.2.P.4. The quantitative information for unit dose must specify a unit of measure for all other ingredients contained in the product.

Another issue that may need to be addressed is with regard to the justification of the excipient function in the formulation. The reported function should be based on documented evidence and the design of the product. For multifunctional excipients, the sponsor should provide the basis of the function intended in the proposed formulation. Based on the intended function, specific controls should be included in the excipient specifications. The assigned excipient function in the original filing will have regulatory implications with respect to post-approval changes depending on the function of the excipient (i.e., recommendations found is SUPAC-IR) (3). An example of a common multifunctional excipient is starch which may be used for multiple purposes (binder, disintegrant, etc.).

Additionally, for complex products (e.g., modified-release products, etc.) with multiple processing steps, it is recommended that the composition of the "intermediates" (e.g. granules, tablet cores or beads) be separated out to reflect each major process step in the composition table for ease of review. Also, it should be clear which ingredients will be added intragranularly or extragranularly. The QbR Frequently Asked Questions (FAQ) document and the Guidance for Industry on Submitting Documentation for the Manufacturing of and Controls for Drug Products provide additional insight (4, 5).

A topic that should also be addressed is related to the chosen dosage form. To be a generic, the dosage form must be the same as the approved RLD unless under an approved suitability petition, and this is clearly one of the main Quality Target Product Profile (QTPP) tenets. With this being said if the RLD is a capsule, the generic must also be a capsule, and also meet the definition in CDER Data Standards Manual (6). Similarly, a formulation may not be called a cream unless it meets the Data Standards Manual (monograph) definition of a cream (6).

Overages. One common deficiency is related to a proposed overage of the active. The firm should identify and justify any formulation overages that appear in the final product; and the overage should be further discussed with respect to the manufacturing process in 3.2.P.3. Note that, in general, the only acceptable justification for an overage in the final drug product formulation is if the ANDA sponsor demonstrates the same overage is also observed in the RLD. It is not acceptable to propose an overage to increase the shelf-life of the drug product. Generic sponsors should justify the proposed overage as compared to the RLD. Data that can be used to justify the overage may include comparative assay data on the test and reference products throughout shelf-life and comparative impurity/degradant levels demonstrating similar behavior. Other reported overages such as the use of excess coating solution in order to ensure uniform coating for product performance do require justification, and this information should be reported in the 3.2.P.1 and 3.2.P.3 sections, as applicable.

Comparison to RLD. Although questions with respect to comparability of the formulation to the RLD in certain dosage form are often addressed during filing of the ANDA, with the justification for the allowed exceptions per the Code of Federal Regulations (CFR) is often times lacking. 21 CFR 314.94 (9) (iii through v) includes a list of "exception excipients" or inactive ingredient differences permitted in a generic product when compared to the RLD (7). These regulations must be followed by the applicant in order to meet the requirements of classification as a generic product. In cases where the applicant is using an exception excipient the sponsor must demonstrate that the differences do not affect the safety or efficacy of the proposed drug product, as required by the CFR.

With respect to comparability of the active pharmaceutical ingredient (API) with the RLD product, this is outside the scope if this article, however, good references can be found in the "Orange Book" with respect to pharmaceutical equivalence. (8)

There are a few commonly cited questions with respect to Q1/ Q2 formulations and the use of "exception excipients". For example, the CFR allows substitution or addition of buffer, preservative or antioxidant in a parenteral dosage forms. However, the sponsor needs to be cognizant of the impact of this substitution or addition on the overall product performance.

The QbR FAQ includes additional recommendations for other allowed differences in solution formulations and bioequivalence impact (4). These include the amount of sorbitol or mannitol in an oral solution; the amount of penetration enhancer in a topical product; any Q1 or Q2 differences in an ophthalmic solution; and any Q1 or Q2 difference in inhalation and nasal spray products.

Finally, if there is any additional risk introduced by a proposed generic formulation, comments may be provided to the firm to justify that the use of the excipient will not introduce a higher risk product into the market. Examples may include the use of aspartame, castor oil, peanut oil, colorants (e.g., FD&C yellow #5), or benzyl alcohol, when they are not present in the new drug application (NDA) product.

Inactive Ingredients Database. The information on the IIG website provides the highest level of an ingredient approved for a single unit (2). As the information is for single unit, we highly recommend that the ANDA sponsor exercise caution in using this information in formulating their drug product. The scope of the information provided in the IIG database is limited to the use of an excipient in the Center for Drug Evaluation and Research (CDER) approved product and for this reason it is imperative the sponsor do the requisite due diligence to justify the use of the excipient in their product line. Citing the IIG may be sufficient is most cases but not in all drug products. Having this supportive information in the application will eliminate any question related to this critical concern. In cases, where citing IIG is found to be insufficient, the ANDA sponsor should follow the recommendations provided in the Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients in providing supportive data (9).

Ingredient composition. Per 21 CFR 314.94 [(iii)(a)(9)(v)], the applicant is required to both identify and characterize the excipients in the proposed product demonstrating that they do not impact safety (7). This includes the composition or "make-up" of the ingredients. In many cases, complex coatings, colors, and flavors are proposed for use in the drug product. A composition should be provided in the ANDA or if the information is proprietary, a drug master file (DMF) reference or the composition of such components should be provided by the supplier directly to the Agency. This allows for a through evaluation of the composition of the materials proposed including iron oxides in coatings or other components from a quality and safety perspective. Certification from the manufacturer of coatings should be provided that the components of the coating either are found in the CDER approved products or applicable CFR citations should be provided for the use of these components in the coatings.

With respect to the use of iron oxides, there are times that a sponsor is asked to justify that the use meets the requirements in the CFR. The ANDA sponsor should indicate that their product meets the 21 CFR 73.1200 requirements for exposure of NMT 5 milligrams elemental iron per day (10). It also is recommended that sponsors include the detailed calculation of total daily intake of iron based on the intended formulation. Additionally, there are other requirements in the CFR with respect to quality of iron oxides used including identity, additive mixtures, specifications and impurities (e.g,. arsenic, lead, and mercury). As stated above, the ANDA sponsor should be able to justify use of excipients in their product line by providing supportive data.

Compatibility of excipients with API. With respect to design of the intended product, the lack of understanding of the chemistry and performance of excipients is one of common causes for production failures and recalls. Thus, it is important to study the compatibility of the excipients with the API and understand the critical material attributes prior to finalizing the drug product formulation. Performance characteristics will be discussed in a later section in this article.

• What evidence supports compatibility between the excipients and the drug substance?

In response to this question in 2.3.P.2.1.2 regarding the compatibility of the API with the excipients, the sponsors frequently provide justification for not conducting these studies based on the facts that the excipients are "common" for the given dosage form and the stability data for the exhibit lots are acceptable. Some of the sponsors are found to monitor only the change in the physical appearance of the mixture of API with the proposed excipients. It needs to be understood that the premise of the excipient-API compatibility studies is to provide justification based on mechanistic understanding of chemical interaction of drug substance and excipients and manufacturing process. Thus, justifying excipient compatibility based on end product testing or monitoring changes in physical appearance are not acceptable.

An example of a so called "common" excipient significantly affecting the formulation, is lactose, when used in conjunction with APIs which are primary or secondary amines. The formation of "Amadori" complexes has been found to be detrimental to the stability of many drug products. Polacrillin potassium is another excipient which may form complexes with APIs containing amines based on the manufacturing process (high heat) or pH of the formulation and result in low assay of the active ingredient over shelf life (11). Another relevant interaction that is frequently observed is that of polyols with free carboxylic group containing APIs.

Justification for not performing excipient-API compatibility studies based on the fact that the formulation is similar to that of the reference listed drug has its flaws, too. It is often found that based on the grade and supplier, the impurity and residual solvents profile of the excipients may differ significantly. The sponsors are encouraged to identify the impurities and residual solvents in excipients which have the potential of adversely affecting the quality of the drug product. A few examples of impurities in excipients which may affect the product stability may be the following:

• Levels of methacrylic acid and divinyl benzene in polacrillin potassium

• Residual peroxides in povidone, crospovidone and/or polyethylene glycol

• Heavy metals or other metal reagents in talc.

Control of excipients

There is only a single question in the QbR-QOS pertaining to control of excipients: "What are the specifications for the inactive ingredients and are they suitable for their intended function?" However, despite its apparent simplicity, the question is a poignant one and relates to a critical question in the pharmaceutical development section, 2.3.P.2.2, which plays a role in ensuring the quality of the drug product and its performance based on label claim over the shelf life.

• How were the excipients and their grades selected?

Performance characteristics of excipients. One of the least understood questions in QbR-QOS is perhaps the one in 2.3.P.2.2, where the sponsor is asked to justify the selection of the "grade" of the excipients. Overwhelmingly, the response to this question is that the excipients are USP/NF grade. Another common response is the verbatim information as found in the Handbook of Pharmaceutical Excipients (12) with no specificity to the intended use in the proposed drug product. This question in the QbR-QOS is intended to demonstrate the understanding of the performance characteristics (i.e., excipient performance or functionality related characteristics) of the excipients which may affect the manufacturability of the drug product. The performance characteristics of excipient are based on their form and their physical properties. For example, for a solid excipient that is to be used in dry blending and direct compaction processes, the impact of changing physical parameters such as bulk density, surface area, particle shape and size distribution need to be evaluated and justified. Similarly, liquid excipients may be evaluated for variation in viscosity and pH; and polymeric excipients need to be evaluated for the impact of changes in molecular weight distribution or viscosity, as applicable.

Sponsors may need to avoid using a specific grade of excipient in certain formulations, if its use is discouraged by the manufacturer of the excipient. It has been observed, that excipients have been used in a formulation, when the suppliers certificate of analysis (COA) clearly states that the grade is not intended for the particular dosage form. This is a serious flaw and needs to be clearly justified. An example of this is the avoidance of certain grades of mannitol in parenteral formulations based on manufacturer's information. Another example is Carbomer 934, which is not intended for internal use per the USP–NF monograph (13).

Control of excipients (specifications). The QBR-QOS question in 2.3.P.4 regarding the specifications of the excipients may be regarded as a summing up of the understanding based on the response to the two questions in the pharmaceutical development section, discussed above.

Compendial excipients. The primary requirement for a compendial excipient is that it meets all the USP–NF requirements (13). The sponsors need to continuously monitor the USP–NF for monograph updates to ensure excipient compliance. As part of the USP–NF monographs for excipients there are performance related tests based on the intended use in a dosage form. The sponsors are encouraged to refer the individual monographs, as applicable (e.g., lactose and microcrystalline cellulose).

We often see a discrepancy in acceptance criteria for certain controls between the excipient supplier's certificate of analysis (COA) and the specifications provided by the ANDA sponsor. In these cases, the sponsor needs to clearly provide a justification for their proposed acceptance criteria and any possible impact on the product stability and safety.

Noncompendial excipients. For non-compendial excipients which are comprised of definite mixtures of compendial excipients, the mixture composition and ingredient identifications are requested. Specifications should include all meaningful controls for quality and purity (e.g., identity, assay, impurities, heavy metals etc.) that are found in the individual USP–NF monographs. Additionally, other sources of tests and criteria for non-compendial excipients may include the manufacturer's information, the CFR and the FCC (14, 15). It is often observed that the compendial methods of analysis for the individual components in the mixture may not be suitable in these cases due to interference from the other components. Thus, information regarding the validation of non-compendial test methods for these excipients needs to be provided.

A novel excipient is defined as one which has not been previously approved by the Agency. These excipients are typically approved as part of the new drug approval process. In certain cases a DMF and clinical and safety evaluation (9) is required as a minimum criteria for approval of the excipients. A good reference for the format of an Excipient Master File Guide is the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) (16).

Excipients of animal origin. Bovine or transmissible spongiform encephalopathy (BSE/TSE) statement and country of origin should be provided for excipients of animal origin. For excipients which may be of both animal and vegetable origin, if the firm proposes to switch from one to another in near future, the effect of the switching on the manufacturability of the product should be addressed. Common excipients in this category are Magnesium Stearate, Calcium Stearate and Stearic Acid. Submitting merely the COAs for both grades of the excipient is usually not enough. Sponsors are requested to provide information regarding pharmaceutical development studies which may have been performed to evaluate the product manufactured using both the grades, for appearance (sticking and picking), content uniformity, tablet friability, tablet dissolution (at target hardness) and manufacturing yield, to assure the equivalence.

Retest dates of excipients. This rather simple information is often missing from the submissions. Although this is covered under cGMPs (21 CFR 211), one of the reasons for requesting this information is to confirm that excipients which support microbial grown are tested frequently, preferably once a year.

Reduced testing based on vendor validation. Firms often provide information in their application regarding proposed reduced testing of the excipients, once the vendor has been validated. As valuable as this information is a firm may be reminded in these cases that vendor validation is a field function based on 21 CFR 211.84(d)(2) and not reviewed or approved by OGD (17). The firm is advised to consult with the district office regarding the appropriateness of their vendor validation policy. Acknowledging this in the original ANDA submission is recommended.

Conclusion

This concludes our discussion on the commonly cited deficiencies for sections 3.2.P.1, Description and Composition of the Drug Product and 3.2.P.4, Control of Excipients. It is noted that the deficiencies and comments cited in these sections of the ANDA are not as numerous as in other sections. However, appropriate information in these two sections are crucial in demonstrating that the sponsor has adequate understanding of the QTPP of their drug product and has strived to manufacture a robust formulation with desired performance over shelf life.

1 Numbering in section heads correspond to those in the Common Technical Document (CTD).

Acknowledgments

The authors wish to acknowledge Lawrence Yu, PhD, OGD Deputy Director for Science, and Vilayat A. Sayeed, PhD, OGD Director of Chemistry Division III, for their encouragement and invaluable insight.

Disclaimer

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,* and Robert Iser, M.S., are team leaders, and Devinder S. Gill, PhD, is a deputy director, 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.

References

1. A. Srinivasan and R. Iser, Pharm. Technol. 34 (1) 50-59 (2010).

2. FDA, Inactive Ingredient Search for Approved Drug Products, http://www.accessdata.fda.gov/scripts/cder/iig/, accessed June 30, 2010.

3. FDA, Guidance for Industry: Immediate Release Dosage Forms, Scale-Up and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (SUPAC-IR) (Rockville, MD, Nov. 1995).

4. FDA, QbR Frequently Asked Questions (June 4, 2007).

5. FDA, Guidance for Industry: Submitting Documentation for the Manufacturing of and Controls for Drug Products (Rockville, MD, Feb. 1987).

6. FDA, Data Standards Manual (monographs), Dosage Form, CDER Data Element Number, C-DRG-00201 (Dec. 15, 2006)

7. FDA, "21 CFR 314 Applications for FDA Approval to Market a New Drug," [Content and Format of an Abbreviated New Drug Application, Sec. 314.94 (9)].

8. FDA, "Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book)"

9. FDA, Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients (Rockville, MD, May 18, 2005).

10. FDA, "21 CFR 73 Listing of Color Additives Exempt from Certification", [Synthetic Iron Oxide, Sec. 73.1200].

11. S. Borodkin and M. H. Yunker, Jrnl. of Pharma. Sci. 59 (4) 481-386 (1970).

12. R. C. Rowe, P.J. Shesky, and M. E. Quinn, Eds., Handbook of Pharmaceutical Excipients, 6th ed. (Pharmaceutical Press, July 31, 2009).

13. USP 32–NF 27 (USP, Rockville, MD, 2010).

14. FDA, "21 CFR 170 Food Additives–21 CFR 180 Food Additives Permitted in Food or in Contact with Food on an Interim Basis Pending Additional Study."

15. Food and Chemicals Codex 6 (USP, Rockville, MD, 2010).

16. IPEC-Americas, Excipient Master File Guide (Arlington, VA, 2004).

17. FDA, "21 CFR 211 Current Good Manufacturing Practice for Finished Pharmaceutical," [Testing and Approval or Rejection of Components, Drug Product Containers, and Closures, Sec. 211.84 (d) (2)].

This article represents the views of the authors and not of FDA.