THE PRODUCT QUALITY RESEARCH INSTITUTE

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1 THE PRODUCT QUALITY RESEARCH INSTITUTE EMERGING RESEARCH PROGRAMS AND PROJECTS (AUGUST 1999) DRUG SUBSTANCE TECHNICAL COMMITTEE DRUG PRODUCT TECHNICAL COMMITTEE BIOPHARMACEUTICS TECHNICAL COMMITTEE SCIENCE MANAGEMENT TECHNICAL COMMITTEE COMPILED BY AJAZ HUSSAIN USING INFORMATION AVAILABLE AS OF AUGUST

2 THE PRODUCT QUALITY RESEARCH INSTITUTE DRUG SUBSTANCE TECHNICAL COMMITTEE May 29, 1999 PROPOSED RESEARCH PROGRAM AND PROJECTS Executive Summary: The Drug Substance Technical Committee strives to establish working groups to address critical issues related to regulatory policies for the drug substance. The ultimate goal of these working groups is to develop scientific knowledge that will result in recommendations for changes in regulatory policies that will, in most cases, be less burdensome. Working groups in the following areas are under considerations: (1) specifications and BACPAC are specifications a reliable determinate of performance of drug product? (2) Methods for determining physical attributes starting with particle size; and (3) impurities and how best to detect, identify and quantitative impurities. The projects will be administered by the Drug Substance Technical Committee. The outcomes are intended develop information to allow appropriate post approval changes and to reduce time-tomarket while maintaining identity, strength, quality, purity, and potency. This will be accomplished by utilizing specifications based on data together with knowledge of the drug substance and its properties including those that interact with excipients to produce the dosage forms. The Drug Substance Technical Committee will focus on generation or acquisition of knowledge to support recommendations for regulatory policy changes relative to CMC aspects of the active drug substance as the critical component of the drug product. The overall objective of CMC information developed by an applicant and reviewed by agency staff relative to the active drug substance is to assure its identity, strength, quality, purity, and potency prior to and following its incorporation in the drug product. The challenge to a pharmaceutical manufacturer and to agency review staff is to achieve these public health objectives for the drug substance via a reasonable number of in-process controls and specifications (test, procedure, and acceptance criteria) that may be performed during the manufacturing process. The Drug Substance Technical Committee has strong links to the Drug Product Technical Committee, which is another group that focuses on manufacture of the active drug substance with excipients into a finished dosage form in its packaging. Monitoring of in-process controls and specifications for an active drug substance occurs in accordance with CGMPs and should be associated with suitable validation. Therefore, associated regulatory CGMP requirements and recommendations are of interest to the Drug Substance Technical Committee. A general objective will be to understand the mechanistic basis for empirical observations that are generally accepted, arise from research projects, or are reported in the literature. 2

3 The following general hypothesis serves as a comprehensive umbrella statement which will encompass many research projects in the research program of the Drug Substance Technical Committee; Adherence to CGMPs and a critical comparison of the analytical results encompassing specifications, impurity profile, and relevant physical properties will be adequate to show unchanged identity, strength, quality, purity, and potency of a drug substance in the presence of pre and post approval changes in 1) manufacturing: scale, site, equipment, controls and process; 2) route of synthesis 3) packaging; 4) supplier(s) of drug substance. An emerging approach relative to pre- and post-approval change in the manufacture of the drug substance directs regulatory focus to comparison of critical physical and chemical characteristics of intermediates or drug substance. Physical characteristics become especially important after the final point that the drug substance is fully dissolved in solution. Failure to reject the umbrella hypothesis in certain research projects in the program will support recommendations to allow any change post-approval, providing an appropriate comparison of key attributes has been made and documented for review. Such comparisons may be made using a sufficient number of specifications (test, procedure, limit of acceptance), defined either in the application, supplements, of in compendial monographs. Specific research projects in the research program will reflect the scientific view that different numbers and rigidity of physical property specifications and in-process controls may be developed depending on solubility, stability, and/or permeability characteristics of the drug substance. Data to test these hypotheses may be derived from existing databases (industry and the agency) or proactive involvement in ongoing development programs in collaborating companies and focused research projects. Research projects will emphasize model systems (drugs, and dosage forms) to maximize generalization of the conclusions realized. Specific projects may focus on critical process control steps and their role in establishing drug substance specifications and test methods. Information to study a specific hypothesis may be obtained from retrospective review of publicly available information, from archival records at the FDA, from sponsor databases, or from prospectively designed studies. WORKING GROUP 1. SPECIFICATIONS AND BACPAC. ARE SPECIFICATIONS (INCLUDING IMPURITY PROFILE AND PHYSICAL PROPERTY EVALUATION) A RELIABLE DETERMINATE OF THE IDENTITY, STRENGTH, QUALITY, PURITY AND POTENCY OF A DRUG SUBSTANCE? HYPOTHESIS A core set of specifications (tests, analytical methods, and acceptance criteria) together with impurity profile and physical property evaluation are adequate to assure the identity, strength, quality, purity, and potency of a drug substance. 3

4 QUESTIONS TO BE ASKED Are specifications together with impurity profile and physical property evaluation a reliable determinate of performance of the drug product? Do drug substances that meet the same specifications together with impurity profile and physical properties perform the same in the drug product? How does one arrive at a set of specifications for allowing post approval changes? APPROACH Recently the PhARMA Bulk Active Pharmaceutical Committee published a decision tree on BACPAC (Pharm. Tech. September 1998, page 68). This decision tree suggests approaches for evaluation of material produced via a process change that could result in altering the reporting requirements for post-approval changes in manufacturing of active pharmaceutical ingredients. A presupposition of this decision tree is that if an intermediate or drug substance produced using a process change meets filed specifications and a comparison on impurity profile (per ICH guidelines) and physical properties (API only) show no significant differences, then the API is the same. However, there is no supporting body of evidence for this presupposition. In fact, some experts have argued that only after a API has been successfully manufactured into a drug product that passes use test (dissolution and stability) can the drug substance be assumed the same. This working group will address these questions first by data mining. Cases where the API showed the same physical properties but the drug product failed formulation uniformity, dissolution or stability tests will be analyzed in order to determine a classification system. Cases where drug substances appear to be the same but perform differently will be mined by the working group either participants or the FDA. Cases where differences in physical properties have been relevant for the dosage form employed will be examined. As a possible example of a specific project, attempts would be made to manufacture drug substances that are as different as possible within a set of specifications (impurity and physical properties). These drug substances will then be manufactured into drug product and the differences in dissolution behavior, stability, and possibly and possibly bioavailability determined. Such studies will address the question: Can specifications tell the whole story? OUTCOMES The major outcome of this research will be ratification of the change evaluation process proposed by the PhARMA Bulk Active Pharmaceutical Committee. Cases where specifications (including impurity profile and physical properties) tell the whole story (or do not tell the whole story) will be identified and correlated with 4

5 experience and with bioavailability results. In these cases, specifications can reliably be used to predict drug product performance. Ultimately, these studies will lead to BACPAC guidelines based on good science. WORKING GROUP 2. PHYSICAL ATTRIBUTES (BEGINNING WITH PARTICLE SIZE METHODS) HYPOTHESIS Relevant physical attributes for a drug substance (and a method for reliably determining these attributes) in a given dosage form produced by a defined process can be found. QUESTIONS TO BE ASKED Are drug substance physical properties impacted by process changes before the last point in the process that the drug substance is dissolved in solution? Can changes in analytical methods for particle size be made without regulatory risk? What is the best method to measure particle size for a give type of formulation manufacturing process? Is one particle size method superior to others? How do particle size methods compare? Do reliable methods for measurement of particle size exist? Are there classes of drug substances that always give reliable particle size measurements by a given technique? Could classes be defined as crystalline solid, amorphous solid, etc? What are the main limitations of particle size measurements? What are the main reasons that particle size measurements fail? What are appropriate acceptance criteria for particle size measurements for materials used in different dosage forms? When are particle size attributes necessary? The same questions need to be answered for all other identified physical attributes including polymorphs, solubility, density, and morphology 5

6 APPROACH Recently the PhARMA Bulk Active Pharmaceutical Committee published a decision tree on BACPAC (Pharm. Tech. September 1998, page 68). The decision tree suggests that in the absence of any other change, methods for determining physical attributes can be changed without affecting identity, strength, quality, purity, and potency of a drug substance. Other experts have suggested, however, that this may not be true for all methods. For example, different particle size methods detect different powder characteristics and some spectroscopic methods are insensitive to polymorph. This working committee will attempt to resolve this dilemma. Initially, working group members will review the attributes that particle size methods measure (average size, distribution, shape, electrostatic properties, etc.) and the acceptance criteria for specifications using different methods. The working committee will also determine when particle size is important. Cases where different methods give widely different results or fail to give the same rank order for particle size of a given substance will be analyzed. A study of several representative drug substances by a variety of particle size methods may be required to fully address the questions listed above. Once particle size has been addressed, this approach will be applied to other physical attributes. OUTCOMES Particle size methods that allow meaningful knowledge-based specifications. Particle size specifications that are truly predictive of behavior rather than the less meaningful empirically derived specifications that are common now. WORKING GROUP 3. IMPURITIES HYPOTHESIS Methods are available that allow reliable determination of impurity levels and degradation products at 0.1%. QUESTIONS TO BE ASKED What is the best method for determining low levels of impurities and degradants? What determines the applicability of different methods? What role do process reagents, catalysts and solvents play in impurity determination? Are there any cases where impurities cannot be reliably determined? By what criteria is one analytical method judged to be sufficient? 6

7 When should a better method be developed? APPROACH Recently the PhARMA Bulk Active Pharmaceutical Committee published a decision tree on BACPAC (Pharm. Tech. September 1998, page 68). The decision tree contained the following segment. This segment applies to detecting impurities in substances other than X intermediate or the API. An important question related to this segment is how is a method judged sufficient, and how is a method judge better? Data mining would be the initial approach. Additionally, studies may be required. OUTCOME Determination of the best method for detection of specific types of impurities and degradants. Ability to apply the decision tree proposed by the PhARMA Bulk Active Pharmaceutical Committee. Analytical method sufficient? Yes Yes New impurities or > existing imp. No Yes No Develop better analytical method? No 7

8 THE PRODUCT QUALITY RESEARCH INSTITUTE DRUG PRODUCT TECHNICAL COMMITTEE Draft 8 July 1999 PROPOSED RESEARCH PROGRAM AND PROJECTS The Drug Product Technical Committee has adopted the following general hypothesis as a comprehensive umbrella statement that will encompass several research projects outlined by the committee: Adherence to CGMP s, which include process validation, and appropriately established product specifications are sufficient to assure consistent quality and performance (or equivalence) of drug products that are manufactured at different locations using alternate pharmaceutical unit operations, excipients, and container/closure systems. This hypothesis was formulated to test the current regulatory approach that generally requires additional tests to assure unchanged quality and performance characteristics of a product (compared to products used in clinical trials to establish an acceptable safety and efficacy profile) when manufacturing changes need to be implemented. Over the last thirty years significant advances have been made in establishing causal links between product variables and product performance characteristics and new test procedures have been developed and utilized to control manufacturing processes. These advances in pharmaceutical sciences support a reexamination of current regulatory policies as outlined by the DPTC hypothesis. The committee believes that: 1. Research efforts expended to test this hypothesis will have a positive impact on the quality of pharmaceutical products available to the American public since this hypothesis promotes the concept that quality needs to be built into products, i.e. prevention of quality problems through the application of sound scientific and engineering principles is in the best interest of public health. Other tangible benefits of these efforts include timely introduction of new and efficient manufacturing technologies and resulting cost savings to the industry, the agency, and the public. 2. Application of sound scientific and engineering principles should allow development of appropriate in-process controls and final product specifications that would assure equivalent quality and performance of products manufactured under CGMP s even when manufacturing equipment, process, sites, batch size may need to be altered to accommodate certain economic and/or technological needs of a company. This notion can also be extended to changes in the components and/or composition of product formulation and packaging materials. 8

9 3. Rejection of this hypothesis would identify scientific gaps in the current product development and manufacturing practices. These scientific gaps could then be addressed by subsequent research efforts directed toward identification of tests (both in-process and final product) that need to be replaced by more appropriate tests. Failure to reject this hypothesis should result in a recommendation to the Agency for allowing manufacturing changes it occur without the prior approval supplement process as long as the final product specifications, CGMP s and other established application/compendial requirements are met. The committee recognizes that: 1. Several more narrowly focused hypotheses would need to be developed under the umbrella hypothesis. 2. Research projects should be associated with an appropriate regulation or regulatory guidance documents. This would facilitate translation of research conclusions into recommendations to the Agency to consider changes in the current regulatory policy. 3. It is important to select and design projects such that the anticipated outcomes are realized in a relatively short period and are applicable to a broad segment of the industry. 4. Design and implementation of research studies needs to be carried out by working groups of technical experts. These experts should be selected to represent; (a) appropriate scientific and engineering disciplines necessary to address selected problems, and (b) different perspectives (for example; the agency - CDER, agency - Field, industry-brand, industry-generic, and academia). 5. Data to test these hypotheses may be derived from existing databases (industry and the Agency, through the Freedom Of Information Act process), proactive involvement (of DPTC and its working groups) in ongoing development programs in collaborating companies, and focused research projects under the PQRI. Funding for all research activities would be derived from the PQRI. 6. Design of research projects should emphasize model systems (drugs, dosage forms, and unit operations) that allow for broad generalization of research conclusions. 7. All aspects of a research project need to undergo rigorous review before, during, and after implementation. Resulting recommendations also should be subject to public discussion prior to endorsement by the Technical Committee. Initial Research Projects: Addressing Regulatory Issues Related to Immediate Release Solid Oral Dosage Forms 9

10 More than 70% of the marketed drug products are the conventional or immediate release (IR) solid oral dosage forms. These products have more than a hundred years of development history and significant product development experience exists in the pharmaceutical community. In addition, over the last several years the Agency s research programs have been focused to address certain manufacturing issues related to these products and significant changes have been made in related regulatory policies. The committee agreed that a further research focus on these products is warranted and feasible. Other Technical Committees of PQRI, namely the Drug Substance Technical Committee and the Biopharmaceutics Technical Committee, are also poised to address issues related to these products. PQRI research on these products is likely to benefit the Agency, a very broad segment of the industry, and the public. The primary objective of research programs designed to test the DPTC umbrella hypothesis for IR solid oral dosage forms should be to strengthen or improve the scientific foundations of applicable regulations and regulatory policies. For example, the following regulations and guidance documents may be relevant to projects addressing IR product issues: 21 CFR 211, 21 CFR , SUPAC-IR, Dissolution Testing of IR Products, draft guidance on Stability Testing, draft BACPAC I and II, and the draft guidance on Waiver of BA/BE studies based on BCS. RESEARCH PROJECT # 1. BLEND UNIFORMITY TESTING BACKGROUND Pharmaceutical blending operations are designed to provide uniform distribution of drug particles in a powder blend. In addition to drug content uniformity in the final product, blending operations can also affect certain other product attributes such as drug dissolution and tablet hardness. For a particular powder bed, selected mixing unit and mixing speed setting, the time to achieve an acceptable blend uniformity is identified by determining drug content variability (%RSD) in powder samples obtained from several parts of the blend as a function of mixing time. Sampling and testing of in-process materials and drug products is outlined in 21 CFR Blend uniformity is addressed under this regulation 21 CFR , which states: 21 CFR (a): To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability on the characteristics of in-process material and the drug product. Such control procedures shall include, but are not limited to, the following, where appropriate: (1) Tablet or capsule weight variation; (2) Disintegration time; (3) Adequacy of mixing to assure uniformity and homogeneity; (4) Dissolution time and rate; (5) Clarity, completeness, or ph of solution. 21 CFR (b): Valid in-process specifications for such characteristics shall be consistent with drug product final specifications and shall be derived from previous acceptable 10

11 process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate. Examination and testing of samples assure that the drug product and in-process materials conform to specification. 21 CFR In-process materials shall be tested for identity, strength, quality, and purity as appropriate, and approved or rejected by the quality control unit, during the production process, e.g., at commencement or completion of a significant phase or after storage for long periods. Legal Findings: United States of America Vs. Barr Laboratories, Inc., et al., Civil Action No , Opinion, by the United States District Court for the District of New Jersey Judge Alfred Wolin, dated February 4, An important aspect of drug manufacturing, blend testing gives firms an opportunity to discover and remedy in-process problems before batches reach the final stages of production. Because finished product testing is limited, blend testing is necessary to increase the likelihood of detecting inferior batches......the Court will follow Dr. Gerraughty s testimony and hold that the appropriate sample for content uniformity testing, in both validation and ordinary production batches is three times the active ingredient dosage size... QUESTIONS TO BE ASKED There are several intertwined scientific and regulatory questions related to blend uniformity that need to be addressed: (1) Blend uniformity is tested during process validation studies, is it then necessary to test for blend uniformity for every production batch? (2) What are the most appropriate test methods for assessing blend uniformity? (3) Are there new methods that do not alter composition of a powder blend during unit dose sampling procedure? HYPOTHESIS AND APPROACH The prevailing legal opinion and current regulations suggest that blend testing should be carried out for each production batch to minimize the likelihood of releasing a batch that does not truly meet end product specifications (due to limited end product testing). General manufacturing experience suggests that, for most powder blends, blend testing for every production batch is not necessary and that unit dose sampling using thief can pose significant problems. Therefore, the following hypotheses should be tested; Hypothesis #1: The likelihood of releasing a batch with unacceptable content uniformity is significantly higher when blend testing is not carried out for every production batch as 11

12 compared to when every batch is tested and found to comply with blend uniformity specifications. Hypothesis #2: Near-IR probes or other approaches can be developed for blend testing that can provide appropriate assurance of final blend uniformity and permit the establishment of rational standards unconfounded by the complications of sampling and handling of powder samples. Hypothesis #1 could be tested using existing data. For testing this hypothesis it may be necessary to utilize solid oral dosage forms prepared using: (1) powder blends that are prone of deblending (2) contain a small amount of a drug, (3) mixing equipment of different designs and operating principles, (4) different unit operations following the blending operation, and (5) different dosage forms (capsules and tablets). Other approaches for testing this hypothesis should also be explored. OUTCOME The desired outcome of these research efforts should be to; 1) identify when blend uniformity tests are needed to assure product quality, 2) develop a more effective method for testing blend uniformity when such tests become necessary, and 3) enhance confidence in end product content uniformity. RESEARCH PROJECT #2. MANUFACTURING CHANGES (PRE- AND POST APPROVAL) BACKGROUND The quality and performance attributes of pharmaceutical products depend on a number of formulation and manufacturing factors. During product development, a set of formulation and manufacturing factors and their target values or acceptable ranges are identified through extensive experimentation, testing of resulting product(s), and process validation to ensure acceptable product quality and performance. During routine manufacturing, some, and generally not all, of the identified factors are controlled within established limits through appropriate in-process controls and specifications. Unchanged product quality from batch-to-batch is then assured via adherence to CGMP s, established in-process controls/specifications, and finished product specifications. When a need arises to change formulation and/or manufacturing processes, adherence to established product specifications and CGMP s are not considered, by the FDA, to be sufficient to assure unchanged product performance. For example, a product manufactured after certain changes may meet all established specifications at the time of manufacture but may fail to do so at a later time that may occur prior to the established expiry date for the pre-change product. Similar 12

13 concerns are also present with respect to application/compendial dissolution test specification that may not be sufficient to assure in vivo bioequivalence between the pre- and post-change products. In absence of clear understanding of such failures, the regulatory policies are designed to be conservative to minimize distribution of an unacceptable product to the public. For ensuring unchanged quality and performance the agency generally relies on process validation, accelerated and long term stability, extensive in vitro dissolution tests or in vivo bioequivalence tests (see SUPAC-IR guidance document). QUESTIONS TO BE ASKED 1. How frequently do products that meet established specifications, fail to exhibit acceptable stability and/or bioavailability? An equally relevant question that also needs attention is - how often do products that fail established specifications exhibit acceptable stability and/or bioavailability? 2. What are the underlying mechanisms and patterns of such failures? 3. Can certain drug and/or drug product attributes be used to identify products at high risk of such failures? 4. How should appropriate process controls, in-process and product specifications, and or change protocols be developed to minimize such failures? HYPOTHESIS AND APPROACH The following hypothesis, focusing on immediate release solid oral dosage forms, was developed for addressing the issues outlined above. Adherence to CGMP s, which include process validation, and appropriately established product specifications are sufficient to assure consistent quality and performance (or equivalence) of immediate release solid oral products that are manufactured at different locations using alternate pharmaceutical unit operations, and established excipients. This hypothesis may be evaluated using a combination of approaches such as datamining, mechanistic analysis of product recall databases, and prospective research studies. These efforts should focus on developing a scientific information/approach for manufacturing changes that minimize the likelihood of product failures. OUTCOME The desired outcome of this project is to acquire sufficient information/data to evaluate the proposed hypothesis and to develop a rational framework for managing manufacturing changes that minimizes the likelihood of product failure/recall. The information generated should be sufficient to recommend elimination of SUPAC Level 2 and Level 3 reporting 13

14 and/or testing for immediate release solid dosage forms that are manufactured under CGMP s and meet established specifications. RESEARCH PROJECT #3. PENDING APPROVAL OF THE STEERING COMMITTEE QUALIFYING CHANGES TO CONTAINER/CLOSURE SYSTEMS (SOLID ORAL DOSAGE FORMS) BACKGROUND For many oral solid dose medicinal products, where the sole degradation mechanism is hydrolytic degradation or simple thermal degradation, the key to stability is the prevention of moisture uptake in the form of water vapor. Most such degradation reactions are believed to take place in conjunction with adsorbed free water. In addition, uptake of moisture can cause softening of the tablets and eventually premature swelling or disintegration. Thus, the prevention of water uptake is important for many oral solid dose forms since exposure to excessive moisture can cause changes in the product that may be detrimental to product performance. HYPOTHESIS For drug products in bottles, where the degradation is either by hydrolysis or a simple thermal process, water vapor uptake studies carried out under specified temperature and humidity conditions using dried silica gel can be used to predict the suitability of a certain changes in bottle source or construction. APPROACH The changes to be addressed will be a change from plastic to glass bottles, or if the same grade and source of polymer is used and the change is simply a change in the site of bottle manufacture. If there is no difference in water vapor uptake, or if the water vapor uptake of the new packaging is lower than for the existing packaging, then such studies could be used to justify not undertaking full accelerated stability studies for a change in packaging. Other degradation mechanisms, e.g. oxidation, would not be covered by this proposal. Changing the packaging container or closure currently requires a full stability program, even if the polymer is the same and it is only the (container) manufacturing site which has changed. In changing the packaging for an existing product for which there is a sufficient body of knowledge it should be possible to avoid unnecessary stability testing if the water vapor uptake characteristics of the new packaging are the same or better than the existing packaging. This project will be limited to glass and plastic bottles. Other projects will be required for other packaging types, e.g. blisters, foil strips, etc. 14

15 The weakest part of most packaging is the closure system. With glass bottles, the wall thickness and construction are such as to render the walls of the container effectively impervious to moisture unless there is an obvious defect in construction. For plastic bottles, whilst moisture can penetrate the walls, the rate is most often very low for bottles used for medicinal products compared to penetration through the closure. Thus, the major means of moisture ingress is through the closure. The issue of extractables is outside the scope of this project. For this reason, if the hypothesis is accepted, then the changes in packaging allowed would be limited to either a change from plastic bottles to glass bottles with no difference in materials used in the two caps or tamper evident membrane, or a change between two plastic bottles where the same grade of polymer(s) are used and it only the site of bottle manufacture that has changed. It is suggested that testing for this project be carried on a range of packaging types and sizes, and under a range of temperature and humidity conditions including 40 C/75% RH and Room Temperature 60% RH which are included in the ICH stability guidelines. The concept of similarity in this project relates to water vapor permeability of the closure system. The underlying assumption is that if stability is initially carried out in a packaging system with known moisture uptake properties, then if the pack is changed in certain ways, but the moisture uptake properties are unchanged or even improved then the packaging change should not be detrimental to the product. The issue of drug partitioning into plastic containers (e.g. nitroglycerin tablets) should be addressed during development and it is anticipated that, for a drug product with a sufficient body of knowledge, such information would be available prior to selection of a plastic packaging system. Key points for development of protocol 1. Types of container/closure 2. Model drug formulation (e.g. effervescent aspirin?): a) Sensitive to moisture both chemically and physically to allow a meaningful comparison b) Easy to assay 3. Do we need to consider coated vs. uncoated tablets (different model formulation)? 4. Compare before and after removal of tamper-evident strips or seals 5. How full (how much headspace, etc.)? 15

16 6. Compare results for change of container volume 7. Compare results for change in closure circumference 8. Types of material of construction for: a) Bottle b) Cap 9. Bottle closing torque 10. Backing off during storage 11. Number of containers at each temperature/humidity condition 12. Final temperature/humidity/time matrix 13. Can we use the same test conditions for all types of polymer and size of container and closure? 14. Do we include blisters and foil strips? In a separate project or can we write a combined protocol? 15. Would we want to restrict the scope even further to container/closure systems using the materials used in the current pack; i.e. would we expect the same extractables from a particular polymer regardless of source? 16. Do we need representative(s) from packaging supplier(s) on the working group? 17. Do we need to consider a concept analogous to the sufficient body of knowledge for the drug, i.e. a sufficient body of knowledge for the container/closure materials to take into account some issues related to extractables? (This would apply to many polymers!) 18. A means to predict extractables will be a separate project. 19. Do we need to worry about whether or not the moisture diffusion can occur through the container wall? We are testing the whole pack and if moisture is able to penetrate, regardless of route, we merely need to be able to assess the overall result. 16

17 THE PRODUCT QUALITY RESEARCH INSTITUTE BIOPHARMACEUTICS TECHNICAL COMMITTEE DRAFT (6/30/99) PROPOSED RESEARCH PROGRAM AND PROJECTS Biopharmaceutics is a drug development and regulatory review discipline that focuses on how drug and drug product characteristics impact on release of drug substances from dosage forms and establishment of methods for comparative evaluation of rate and extent of drug absorption. Expressed in terms of regulatory product quality attributes (identity, strength, quality, purity, and potency), biopharmacetuics relates to factors that effect potency or bioavailability of products of established identity, strength, quality, and purity. Therefore, bioavailability (BA) and bioequivalence (BE) may be viewed as product quality/performance specification (attribute, test method, acceptance criteria). Several methods are available to assess BA/BE. These include pharmacokinetic methods, pharmacodynamic methods, comparative clinical trials, and in vitro methods. A specific regulatory research challenge is to validate these methods, to assure that they relate in a well-defined way to safety and efficacy of the active drug substance, and to determine acceptance criteria (goalposts) that are reasonable both from a manufacturing as well as from a public health standpoint. To meet this challenge, the Biopharmaceutics Technical Committee has adopted the following general hypothesis as a comprehensive umbrella statement, which will encompass planned research projects: In vitro and physico-chemical product tests can be developed to assure equivalent rate and extent of drug absorption of many pharmaceutical dosage forms. This hypothesis is designed to expand the application of in vitro approaches in the documentation of BA/BE. The Biopharmaceutics Technical Committee has outlined the following research topics that relate to the umbrella hypothesis. 17

18 PROJECT 1: WAIVER OF IN VIVO BIOEQUIVALENCE TESTS FOR IMMEDIATE RELEASE SOLID ORAL DOSAGE FORMS THAT CONFORM TO IN VITRO DISSOLUTION SPECIFICATIONS THAT ARE ESTABLISHED TO ASSURE IN VIVO BIOEQUIVALENCE. BACKGROUND The Code of Federal Regulations (21 CFR ) provides criteria for a waiver of evidence of in vivo bioavailability or bioequivalence (biowaivers). Under certain conditions, biowaivers may be granted for oral solution dosage forms and DESI effective products that are not considered bio-problem products (21 CFR ). For certain other products biowaivers may be justified through demonstration of a reliable (i.e., predictive of in vivo bioavailability) correlation between an in vitro test method, such as dissolution test, and in vivo bioavailability data. Unless intestinal permeability and other factors affecting absorption are considered, in vitro-in vivo correlations are expected only when the dissolution process is sufficiently slow to be rate determining and the selected in vitro test method emulates, at least to some degree, the in vivo drug dissolution processes. It has often been observed that when such empirical correlations are developed (e.g., extended release products or slow dissolving IR products of poorly soluble drugs) these tend to be formulation-specific. The most widely applied dissolution test methods for IR products are based on the USP s apparatus I (basket) or II (paddle) at agitation rates of 100 and 50 rpm, respectively. Typically, 900 ml of water or 0.1 N HCl are used as dissolution medium. Historical in vitro - in vivo comparison data suggests that these methods are generally sensitive to formulation factors that affect drug dissolution process and often it is observed that two products that may exhibit some dissolution differences, in vitro, provide similar blood drug concentration time profiles. However, in a few instances significant differences have been observed in the blood level profiles of two products that meet current application or compendial dissolution specification. On rare occasions an inverse in vitro - in vivo relationship, i.e., higher peak drug concentration in blood for a product that exhibits relatively slow rate of dissolution in vitro compared with another product, have also been observed. If the regulatory utility of dissolution tests for IR products are to be expanded, their reliability must be improved. This may be achieved by considering the mechanistic relationships between drug dissolution, physico-chemical characteristics of drugs, gastrointestinal physiology and absorption. QUESTIONS TO BE ASKED 1. How frequently do two pharmaceutical equivalent IR dosage forms that conform to established in vitro dissolution specifications fail to meet the in vivo bioequivalence acceptance criteria? 18

19 2. What are the underlying mechanisms that lead in vivo bio-in-equivalence? 3. Do certain excipients, on the current Inactive Ingredient Guide list, alter drug absorption? 4. Do certain formulation differences lead to subject-by-formulation interactions? HYPOTHESIS Using currently available compendial dissolution apparatus, in vitro dissolution test specifications that assure in vivo bioequivalence can be developed for conventional (or immediate release) solid oral dosage forms. APPROACH The underlying theme of this research project is that for majority of drug products, that containing typical excipients in vitro dissolution test is a more sensitive discriminator of in vivo performance, providing suitable test conditions are employed. Through the support of its research program, the agency has already taken steps in this direction and issued a draft guidance document entitled Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Containing Certain Active Moieties/Active Ingredients Based on a Biopharmaceutics Classification System. When finalized, this guidance will identify rapidly dissolving products containing highly soluble and highly permeable drugs as candidates for waiver of in vivo BE tests. The (agency s) reasons for limiting the utility of in vitro dissolution test for waiver of in vivo BE to identified class of drugs/products should be used in developing research projects to evaluate the proposed hypothesis. OUTCOME The desired outcome of this project is to develop information/data to address public health concerns associated with the use of in vitro dissolution test to assesses in vivo bioequivalence and to develop an approach for dissolution testing that will assure in vivo bioequivalence. In vitro tests to document BA/BE for immediate solid oral dosage forms will reduce the need for clinical testing in healthy human volunteers and conserve industry and agency resources without affect public health expectations for continue BE in the presence of change. 19

20 PROJECT 2: IN VITRO METHODS TO ASSESS BA/BE OF TOPICAL PRODUCTS BACKGROUND Bioequivalence is defined at 21 CFR as the absence of a significant difference in the rate and extent to which the active ingredient or the active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. A BE determination involves a comparative assessment of the release of the drug to the site of action between a test (T) and reference (R) product. While BA is measured in the IND/NDA period, BE may need to be established in NDAs, ANDAs, and in the presence of post-approval changes for both NDAs and ANDAs. Bioequivalence assessment of topical products, and other locally acting drug products, poses significant challenges. With respect to topical products, two novel methods have been proposed for regulatory applications. 1. FDA has published a guidance entitled SUPAC-SS Nonsterile Semisolid Dosage Forms. Scale-up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation (May 1997). This guidance recommends additional tests and filing documentation to support post-approval changes in components and composition and method of manufacture of topical products. An in vitro release test is recommended to document unchanged product quality and performance. The measured drug release rate is considered to be a property of the dosage form and reflects the combined effects of several physical and chemical parameters, including solubility and particle size of the active ingredient and rheological properties of the dosage form. 2. A draft guidance for industry entitled Topical Dermatological Drug Product NDAs and ANDAs -- In Vivo Bioavailability, Bioequivalence, In Vitro Release and Associated Studies (Issued 6/18/1998) recommends the use of a tape-stripping method termed Dermatopharmakokinetic (DPK). This method is carried out in healthy subjects with intact skin and is considered as a rigorous approach for determining BE. Several concerns have been raised with respect to the utility of these methods. In order to pursue its overall goal of developing predictive in vitro methods, the Biopharmaceutics Technical Committee proposes to further evaluate simultaneously the two proposed methods (in vitro release and DPK). QUESTIONS TO BE ASKED 20

21 1. Why should product testing in vitro and/or on intact skin (DPK) be considered relevant for predicting product performance in patients with different degrees of skin damage and/or different anatomical sites (e.g., follicle-targeted topical products)? Alternatively, what is the clinical relevance of DPK and in vitro release test? 2. Can in vitro release rate be correlated to DPK and/or clinical measures of products safety and efficacy? HYPOTHESIS In vitro drug release test can be a suitable indicator of BA/BE of topical products. APPROACH In vitro drug release tests proposed in SUPAC-SS should be evaluated for its ability to discriminate between bioinequivalent topical products. Topical corticosteoids products may serve as model products since a reasonable pharmacological endpoint is available for assessing their in vivo performance. Studies linking in vitro release tests to the proposed skin-stripping method to quantify skin levels of drugs and the in vivo clinical performance will greatly enhance our understanding of the value of tests methods. Research projects to address other concerns (e.g., anatomical site) should be designed. OUTCOME Availability of in vitro tests that predict in vivo performance of topical products will be a significant advance in the regulation of these products. This will reduce reliance on costly and insensitive clinical trials for bioequivalence assessment and improve product quality and performance. PROJECT 3: IN VITRO METHODS FOR ASSESS BA/BE OF NASAL AND INHALATION DRUG PRODUCTS HYPOTHESIS Critical product characteristics that impact bioavailability can be identified and utilized to develop test methods and measures to accurately assess bioequivalence. PROPOSAL 21

22 Identify critical in vitro performance characteristics of selected model systems for which comparative in vivo performance data is available. Multisource (foreign and domestic) Albuterol MDI and Proventil - HFA may serve as a suitable model. The objective would be to develop criteria to base meaningful specifications for spray pattern, plume geometry, and particle size distribution differences. These efforts should also address different test methods for assessing in vitro performance. For example, comparative evaluation of the following methods for particle size distribution may be performed: 1) cascade impactors; 2) laser diffraction; 3) time of flight laser. An additional component of this research will be to develop suitable metrics and statistical approaches to allow comparisons. These approaches should have clinical safety and efficacy relevance. IMPACT Availability of in vitro tests that predict in vivo performance of nasal and inhalation products will be a significant advance in the regulation of these products. This will reduce reliance on costly and insensitive clinical trials for bioequivalence assessment and improve product quality and performance. 22

23 THE PRODUCT QUALITY RESEARCH INSTITUTE SCIENCE MANAGEMENT TECHNICAL COMMITTEE Draft November, 1998 An overall objective of the drug development process is to manufacture a high quality, optimally performing drug product. The drug product contains one or more active moieties that creates the safety and efficacy statements that appear in product labeling. In addition, the drug development process are also establishes a series of specifications (attribute, analytical process, and acceptance criteria). Specifications are abstracted form a large body of information that may be part of a drug development report. The overall effort, to include scale-up and validation at the time of market approval, as well as postapproval change, will be the general subject of the Science Management Technical Committee. This Committee has adopted the following general goal to guide the development of its program and projects: The goal of this technical committee will to develop strategies that maximize the efficiency of the processes that produce an optimally performing drug product that meets public health objectives for identity, strength, quality, purity, and potency. The following four projects were identified and approved by the Steering Committee. 1. Process Mapping CMC and Biopharmaceutics Review 2. Crisis and Risk Management 3. New Models for Product Updating (4. Information Technology) 1. PROCESS MAPPING THE REVIEW AND DEVELOPMENT PROCESS PURPOSE Process map the CMC and Biopharmaceutics review and approval processes as well as process map typical industry CMC and Biopharmaceutics development. The goal is for drug developers and agency reviewers having a greater understanding of each other s processes so that opportunities can be identified for optimum interactions and data and information sharing. DELIVERABLES 23

24 An FDA CMC and Biopharmaceutics review and approval process map detailing the key events and activities throughout the process, inputs, outputs, responsibilities (e.g. contributors, reviewers, approvers), and measurements (e.g. time, cost, quality). A typical process map of CMC and Biopharmaceutics drug development as generally represented in new molecule product development in the pharmaceutical industry. Recommendations from the working group for changes in the review and approval process and submissions and content changes, approaches, timing changes, opportunities in electronic communication and data transfer, and new methods BENEFITS More streamlined and efficient review process Greater understanding between industry drug developers and FDA reviewers as to the needs, constraints, and opportunities for improvement in FDA reviewer and drug developer interactions Information sharing paradigms that can speed both drug development and drug review TIME Project completion and recommendations to the Steering Committee within one year of populating the Working Group BUDGET A part time administrative assistant would be needed to accumulate information, writeup reports, collate data, etc. Members of the Working Groups will need to cover their traveling expenses themselves. If none of the Working Group members have experience in process mapping, it may be necessary to bring in a consultant for training the group and getting the process started. Administrative Assistant $15,000 Process Mapping Consultant $15,000 Total $30,000 CONSTRAINTS Requires that Working Group be staffed by the more experienced Agency reviewers. In addition, these individuals must have sufficient time to spend on the project. 24