Abstract
Approved drug products may be subject to change(s) for a variety of reasons. The changes may include, but are not limited to, increase in batch size, alteration of the drug product constituent(s), improvement in the manufacturing process, and shift in manufacturing sites. The extent of pharmaceutical testing and the regulatory pathway for timely implementation of any change in the approved product and/or process depends upon the nature and extent of change. The U.S. Food and Drug Administration (FDA) has published guidelines that outline its expectations for the Scale-Up and Postapproval Changes (SUPAC) in the solid oral immediate and modified release (MR) products, and semisolid formulations. However, to date, no such guidelines have been issued to address SUPAC in the orally inhaled drug products (OIDPs), and this article represents a seminal contribution in this direction. It is hoped that it will inspire contributions from the relevant multidisciplinary experts from the pharmaceutical industry and the agency in accomplishing formal regulatory guidelines relevant to the OIDP SUPAC. The OIDPs are complex drug–device combination products. Therefore, a conceptualization of SUPAC guidelines for these products warrants consideration of contributions of effect of change(s) in individual components (drug substance, formulation, device) as well as a compound effect that a single or multiple changes may have on product performance, and its safety and efficacy. This article provides a discussion of scientific aspects and regulatory bases relevant to the development of SUPAC for OIDPs, and it attempts to outline considerations that may be applicable in addressing issues related to the OIDP SUPAC in the context of human drugs. The authors’ statements should not be viewed as recommendations from any regulatory agency, as the applicable guidelines would be determined on case-by-case evaluation by the relevant authorities.
Introduction
Drug development and approval constitue a lengthy, sequential, complex, and extensively resource-intensive undertaking. 1 It begins with the discovery of a molecular entity with potential to provide certain therapeutic benefit identified through extensive preclinical testing. The pharmaceutical experts use the results of preclinical testing to determine how to best formulate the drug for its intended clinical use. Regulatory agencies require testing that documents the key characteristics such as chemical composition, purity, quality, and potency of the drug product’s active ingredient(s) and the formulation. From a regulatory perspective, the postdiscovery establishment of chemistry, manufacturing, and controls (CMC), the drug’s pharmacological profile and toxicological properties, as well as evidence for clinical safety and efficacy are required for approval of all drug products.
All drug development programs are subject to changes that may be planned in advance or are instituted due to unforeseen developments in, but not limited to, the drug product constituents, batch size(s), technical staff, and manufacturing process, as well as site(s) of manufacturing. Such changes that might occur during product development and postapproval may be prompted by business strategies, and/or originate from advances in science, technology, and regulatory arenas. Regardless of the cause and origin, alterations in drug products warrant deliberations of relevant logistics, scientific challenges, and regulatory complexities pivotal to the accomplishment of product development with efficiency, minimum patient impact, and reasonable resource investment. At any stage of product development, the efficiency of implementation of necessary changes is enhanced by a clear understanding of the applicable regulatory requirements.
The regulatory agencies furnish their advice through product development meetings solicited by the sponsors, workshops/conferences, or publication of the applicable guidelines. The U.S. Food and Drug Administration (FDA) has previously published guidance documents addressing the scientific testing needs and regulatory submission requirements to accommodate the Scale-Up and Postapproval Changes (SUPAC) in the solid oral immediate release (IR) 2 and modified release (MR), 3 and semisolid 4 drug products. The agency has subsequently issued guidances for consideration relevant to changes in drug substances 5 as well as biological products.6,7 The testing requirements and regulatory submission categories vary with product class and level of change.
SUPAC are important regulatory considerations due to the possible relevance of the change(s) to the drug products’ safety and efficacy. Responsibility for determination of any change essentially lies with the applicants/authorization holders. Pursuant to 21 CFR 314.70(a), the applicant must (1) notify the FDA about each change in each condition established in an approved NDA beyond the variations already provided for in the application, and (2) assess the effects of the change before distributing a drug product made with a manufacturing change. The regulations require submission of supplement and its approval before distribution of the product made using major change(s) in the drug substance, drug product, production process, quality controls, equipment, or facility that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product [21 CFR 314.70(b)(1)]. Furthermore, as per 21 CFR 314.70(b)(2), the changes include, but are not limited to, (i) qualitative and/or quantitative changes to formulation of the drug product, including inactive ingredients, or in the specifications provided in the applications, (ii) changes requiring completion of studies to support equivalence of the drug product when manufactured without the change or to the reference listed drug (RLD), (iii) changes that may affect drug substance or drug product sterility assurance, such as changes in drug substance, drug product, or component sterilization method(s) or an addition, deletion, or substitution of steps in an aseptic processing operation, and (iv) changes in the synthesis or manufacture of the drug substance that may affect the impurity profile and/or the physical, chemical, or biological properties of the drug substance. Relevant to the orally inhaled drug products (OIDPs), the regulation also includes recommendations for changes to the container closure system (CCS)/device that controls the drug product delivered to a patient [21 CFR 314.70(b)(2)(vi)], including the changes in the type and/or composition of a packaging component that may affect the impurity profile of the drug product.
The regulations mandate that the applicant obtains approval of supplement from the FDA before distribution of a drug product made using a change, except for minor changes that can be documented in an annual report [21 CFR 314.70(B)(2)(d)] and considered to have minimal potential to have an adverse effect on the identity, or strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product, or submission of protocols for describing the specific tests and studies [21 CFR 314.70 (B)(2)(e)]. Depending upon the risk from the change, reporting requirements are grouped into three broad categories, including (A) minor changes that can be reported in annual reports [21 CFR 314.70(d) and 314.81(b)(2), (B) moderate changes that require submission of supplement for changes being effected (CBE-0), or changes being effected in 30 days (CBE-30) [21 CFR 314.70(c), 314.70(c)(3), and 314.70(c)(6)], and (C) major changes that require submission of a prior approval supplement [21 CFR 314.70(b) and 314.97(a)].
Although the responsibility of reporting postapproval changes lies with the application holders, the drug–device combination nature of OIDPs adds complexity as the reporting requirements may vary with the constituents of the products. For example, the information regarding the drug substance, CCS, or device component(s) may exist in specific Drug Master Files (DMFs) or it may be submitted as part of the application. If the information is contained in associated DMFs, letters of authorization would be necessary to allow the applicant to reference the DMF. In addition, the DMF holders are responsible for notifying each person authorized to reference the DMF about the nature of the change. The authorized persons determine the impact of each change in the DMF to each condition established to the application and how to notify (in the annual report or as a supplement) the agency of the changes to their approved applications. If the information is contained in an application, changes in the information are submitted in the form of a supplement to the approved application or in an annual report, whichever is appropriate for the change being made.
The nature of CMC development/characterizations and clinical testing vary with the drug product, route of administration, and its intended use. In this regard, drug products made for delivery through the inhalation route represent a class of “complex drug products” due to the drug–device combinations required to deliver drugs in the form(s) that allow delivery to the intended site(s) of action in the lung. Among the combination products for inhalations, metered dose inhalers (MDIs) and dry powder inhalers (DPIs) are the most extensively used by the patient populations. Although the MDIs have been marketed since 1956 8 and the first DPI was introduced in 1967, 9 the FDA did not issue guidance related to CMC for these products till 1998 10 —with subsequent revision 20 years later. 11 Furthermore, to date, the agency has not issued any SUPAC guidelines for OIDPs. Need for agency guidance on OIDP SUPAC guidance has been expressed among relevant experts. 12
A notable difference between the U.S. FDA’s 1998 and 2018 CMC guidances is the introduction of the word “quality” in the title and text of the revised document issued in 2018. That is an outcome of significant advances in the science and regulatory arena focused on the drug products’ quality during development and postmarketing. The regulatory innovations triggered by the U.S. FDA’s launching of the Critical Path Initiative,13,14, introduction of Process Analytical Technology (PAT) 15 and Quality-by-Design (QBD),16–18 and the agency’s expectation for their incorporation into product development by the industry as well as the regulatory review process constituted a tremendous force to enhancing product quality. The agency’s SUPAC guidances for solid oral and semisolid products were developed before the stated advances in science, and they have not been updated to incorporate valuable insights from the FDA’s focus on QBD. However, the industry has paid due attention to application of PAT and QBD to high-quality product development and SUPAC. 19
The discussion below takes into consideration the multidisciplinary advances in science related to the development of the OIDPs, updates in the relevant regulatory guidelines, and conceptualizes rational approaches to address SUPAC in the OIDPs.
SUPAC Considerations for OIDPs
Scientifically sound drug product development yields high-quality therapeutics with flexibility that allows maintenance of quality to assure safety and effectiveness even under the circumstances that would dictate changes in the product during development, under approval, and postapproval. Regulatory guidelines for OIDP SUPAC are needed for a variety of reasons, but not limited to, reduced need for postapproval changes, improved product quality in product development, and enhanced quality of commercial products. 20 The desired flexibility in instituting postapproval changes can be created by establishing operational boundaries for the relevant processes and parameters during product development. These limits define range(s) over which changes in the processes and/or parameters would not affect product performance. Each established range represents a “design space” for a given process or parameter or combination thereof—a cardinal feature of the QBD paradigm. 21
Design space is determined and proposed by the applicant, and it is subject to regulatory assessment and approval. Application of QBD to product development entails an understanding of the products from the patients’ perspectives and establishment of the relevant drug product critical quality attributes (CQAs) and understanding the relationship between formulation and manufacturing variables. Operation of the CQAs within the validated design spaces is directly relevant to maintenance of product quality with respect to its safety and efficacy. Adherence to design spaces established during product development ensures continued product quality through shelf-life. 19 Furthermore, SUPAC within the established design spaces would carry minimal regulatory commitment. However, maneuver(s) outside of the design spaces constitute change(s) that would normally initiate the applicable regulatory change process for the intended change.
Key elements of the QBD paradigm include identification of product quality attributes (PQAs) determinant of the quality target product profile (QTPP). It outlines the desired characteristics of a target product by defining the intended use, target population(s), and other desired attributes, including safety- and efficacy-related characteristics. 22 The QTPP establishes the basis of product development with the consideration of the finished product. 23 The PQAs represent qualities directly related to the use, including safety, efficacy, and stability. The PQAs are influenced by CQAs, which represent the physical, chemical, biological, or microbiological property or characteristics that should be within an appropriate limit, range, or distribution to ensure the desired and sustained product quality. 24 In addition, critical process parameters, whose variability may impact one or more CQAs, are monitored and controlled to ensure the process maintains the desired quality. An understanding of relationship between these quality elements is essential to their rational application to scale up and other changes.
Application of QBD to development and approval of inhalation products may reduce overall approval time, and introduce flexibility in the manufacturing system thereby reducing the probability of product failures postapproval.20,25 However, the process is complicated by the drug–device complex nature of the OIDPs. Each process that links to manufacturing from physicochemical properties of the input material to packaging might have its own design space. 26 Thus, an OIDP may have a multitude of applicable design spaces. A detailed discussion of these well-established scientific principles is unnecessary in view of the extensive coverage of QBD and its applications in the scientific literature, FDA guidances, and the various International Council of Harmonization (ICH) guidelines. Instead, the following sections are devoted to scientific and regulatory deliberations for development of SUPAC proposals for the OIDPs to include MDIs, DPIs, and soft mist inhalers (SMIs); the nebulization-based combination products are not included in this article. The layout of our proposal is based on the established regulatory format with respect to classification of SUPAC at Levels 1, 2, and 3.
SUPAC recommendations for non-OIDPs2–4 include considerations for postapproval increase in batch size because the commercial batches in most cases may be much larger than the clinical/exhibit batches. However, that may not be the same for OIDPs. To the authors’ knowledge, the clinical/exhibit batches used in the development of OIDPs are generally manufactured at about one-third or at half the anticipated commercial sizes. Accordingly, commercial scale manufacturing is established proactively to support pivotal clinical studies. 27 Postapproval increase in batch size (if any) is rare and generally of modest magnitude (2–3×), compared with the 10× or more commonly used for solid oral products. Nevertheless, scale-up changes, if warranted, during the OIDP development (R&D—technology transfer—manufacturing) would be product-specific even within a product class (MDIs or DPIs or SMIs). However, CQAs relevant to the determination of the impact of any scale-up changes might be the same as those recommended below for assessment of the influence of postapproval adjustments. Therefore, the discussion below is focused on postapproval changes.
Postapproval changes are submitted to the agency’s division/center, which approved the drug product. The drug products discussed in this article are drug–device combinations. The FDA review of combination products typically is a multicenter collborative activity to include the Center for Drug Evaluation and Research (CDER), the Center for Devices and Radiological Health (CDRH), and/or the Center for Biologics Evaluation and Research (CBER). The agency’s Office of Combination Products is responsible for processing of intercenter consult requests beginning with assignment of a lead agency center. 28 For the OIDPs, CDER is the lead center with CDRH as consult.29,30 For example, see approval package for LONHALA™ MAGNAIR™ (glycopyrrolate inhalation solution) that was approved by the Division of Pulmonary, Allergy, and Rheumatology Products in CDER as the lead center, however, in consultation with CDRH for device evaluation. 31
Metered Dose Inhalers
Therapeutic MDIs are drug–device combination products that carry drug formulation contained in the CCS. The PQAs that constitute the MDI QTPP include efficacy, safety, and stability, which are contributed by a variety of CQAs and critical material attributes (Table 1). Both formulation and device contribute to the desired performance of MDIs in terms of the delivered dose, content uniformity, aerodynamic particle size distribution (APSD) of the delivered aerosol, chemical and physical stability of the drug over the product shelf-life, and extent of leachables from device components. 32 Thus, the scientific considerations for assessment of postapproval changes are separately considered for the formulation and device components (Table 2).
Metered Dose Inhaler Product Quality Attributes, Relevant Critical Quality Attributes, and Critical Material Attributes
APSD, aerodynamic particle size distribution; CCS, container closure system; CQA, critical quality attribute; PQA, product quality attribute.
Metered Dose Inhaler Quality Attributes Related to Postapproval Changes
MDI formulation contains drug substance(s) and volatile propellants.33,34 In addition, some products may contain cosolvents, 35 lubricants, 36 suspending agents,36,37 and surfactants. 38 The available SUPAC guidances2–4 do not include discussion dedicated to drug substances. However, SUPAC consideration for OIDPs warrant deliberations upon drug substances because (1) their properties are relevant to aerosolization of the formulations and (2) the aerosolized drug particles are delivered intact to the local target site (lung), unlike the solubilized form of drugs delivered through systemic circulation upon administration of oral products. Thus, the discussion below entails consideration of the various components and the relevant CQAs listed in Table 2 in terms of possible changes that might occur postapproval. Analytical testing or other studies that might be required to support the changes and the applicable regulatory pathways are summarized in Table 3.
Examples of Postapproval Changes in Metered Dose Inhalers, with the Relevant Testing and Regulatory Considerations
With appropriateness and adequacy by seeking timely advice from the relevant regulatory agency.
Regulatory compliant product development, including use of adequately validated methods and applicable current Good Laboratory Practices (cGLP) and good Manufacturing Practices (cGMP).
BE, bioequivalence; CMC, chemistry, manufacturing, and controls; E&L, extractable/leachable; DDU, Delivered Dose Uniformity; MOC, material of construction.
Drug substance
The drug substance commonly referred to as an active pharmaceutical ingredient (API) is the formulation constituent most relevant to the safety and effectiveness of any drug product. The FDA guidance enlists a number of attributes usually tested at release and on stability of APIs used in MDIs and DPIs. 11 However, key considerations for the development of MDI formulations include interfacial properties, physicochemical characteristics of the drug substance, such as solubility profile, particle size, morphology, and density. 39 The API properties may be influenced by the quality of raw materials, intermediates, and precipitation and purification processes used during synthesis/manufacturing.40–42
This article does not delve into the aspects of good manufacturing practices (GMP) for the API and intermediates but refers the readers to the applicable ICH guidance on GMP for APIs. 43 In general, the expectation is that for chemically synthesized small-molecule APIs, GMP starts from the designated starting materials; however, for APIs derived from other sources (animal sources, plant sources, herbal extracts, fermentation, or cell culture techniques), GMPs are applied earlier in the process on a case-by-case basis.
Drug substance particles in manufactured mother lots of APIs are usually greater in size by order of magnitude than the range suitable for pulmonary deposition. Micronization of APIs for inhaled drugs is used to attain the desired particle size, typically 1–5 µm. Jet milling is the conventional approach commonly used for mechanical micronization of drug particles for pulmonary delivery. The starting point for desired micronized product is crystalline API input for micronization. Optimization of crystallization in all aspects is relevant to consistent particle size and morphology of the input material.
Particle reduction by micronization is a complex process, the outcome of which is influenced by several factors/process that are relevant to SUPAC. Micronization is affected by geometry of the mill design (shape, number and angle of grinding nozzles, diameter of grinding chamber), environmental conditions, size classification, mechanical properties of the input material, and process parameters, including material feed rate, Venturi feed pressure, and grinding pressure. 44 Micronization by milling imparts high energy to the API causing mechanical activation that induces surface disorders, either as crystal defects or amorphous sites at the surface of the particles.45–47 Disordered sites on the micronized particles, which can recrystallize during storage at high-humidity environments,48–50 are relevant to aerosolization,51,52 as well as the long-term stability of the drug substance.53,54 High energy induced by the milling process must be dissipated before use in product development/manufacturing, as it affects both APSD and formulation stability. 55 The heightened energy of the freshly micronized API can be dissipated by allowing the drug substance to relax upon storage at controlled conditions with respect to relative humidity and temperature 56 to promote conversion of amorphous to crystalline content. 57 The level of energy and the extent of relaxation necessary to achieve stable API may be both drug and process dependent. 58
The QBD-based product development approaches construct safe boundaries for the physicochemical properties of the drug substance manufacturing and micronization over which the pertinent CQAs may be unaffected by variations within these boundaries. 59 The API manufacturing also yields the drug-related substances or impurities, which may originate from the raw material,60,61 manufacturing process,62,63 a variety of degradation processes,64,65 and inadequate storage. 66 In addition to chemical purity, the impurities may affect polymorphic form, particle size, and morphology of the API. 57 The physical and chemical properties of the drug substances may also change upon relaxation/conditioning.
Any change in manufacturing, particle size reduction, or postmanufacturing processing and storage can potentially introduce multiple changes affecting the chemical and physical integrity of the drug substance. Table 3 provides a few examples illustrating the changes, the impact they can have on the relevant CQAs, and the regulatory requirements applicable to implementation of the changes. A fundamental regulatory consideration to manage the risk would be a requirement for equivalence between the approved and modified APIs. Postmodification batches that exhibit chemical attributes comparable with established data may pose less risk than batches with deviation from historical data. Similarly, modified material that has the same physical properties may pose lower risk than postmodification material with different physical properties (e.g., solid-state form, particle size, solubility, bulk/tapped density). 5
Deviations in the physicochemical properties of APIs may affect the drug delivery attributes relative to safety and efficacy. The need for, and extent of, testing required to support any change will depend upon the level of change and relationship (if any) between change and the relevant CQA. Changes within the established design spaces may not evoke, or provide a reduced, regulatory action such as a CBE or documentation in the annual report. Deviations from the established ranges would require in vitro testing to support changes, and the testing requirements may escalate to include in vivo (human) studies (Table 3). The nature of applicable in vitro and human studies is separately discussed later in this article (see the section on In Vitro and In Vivo Testing to Support SUPAC).
Excipients
As stated above, all MDI formulations contain volatile propellants, while some products may contain additional excipients. Of these, the propellant constitutes the largest in volume and by weight. Furthermore, it is the excipient most relevant to drug delivery from the MDIs, which rely on the driving force of the propellant to atomize droplets containing drug and excipients for deposition in lungs. 32 Choice of propellant used in MDIs can be drug and/or formulation specific. Furthermore, development of new products includes selection of device and CSS components compatible with the propellant.
Thus, in practice, a propellant once chosen remains unchanged through the life of the approved product. In addition, development of the follow-on (generic) MDIs also use the same propellants to comply with the qualitative sameness (Q1) requirement for the aerosol formulations. Therefore, changes in propellants in the approved MDIs do not occur, unless enforced upon by environmental concerns, including the Chlorofluorocarbon (CFC) to Hydrofluoroalkane (HFA) change in the mid-90s because of the ozone layer depleting potential of the CFC propellants, and the currently undergoing shift from the global warming potential of the HFA propellants 227 (1,1,1,2,3,3,3-heptafluoropropane) and 134a (1,1,1,2-tetrafluoroethane) used in the approved MDIs to HFA 152a (1,1-difluoroethane) and HFO1234ze (Trans-1,3,3,3-tetrafluoropropene), which are the propellants with much lower global warming potential. Thus, propellant change is unlikely to constitute a postapproval change. However, if any changes occur at the manufacturing (supplier) level, the extent of deviation(s) from the relevant DMF would be the determinant of the impact of change. Changes in the established propellants are likely to remain within established acceptable ranges. Nonetheless, if the changes do occur, the testing might include determination of pre- and postchange equivalence of key attributes, including drug compatibility, vapor pressure, and material compatibility and flammability. The impact of change will warrant case-by-case evaluation, because the propellant change may affect a multitude of CQAs related to the safety and efficacy of MDIs, including labeling.
Excipients used in MDIs also include, but are not limited to, ethanol, lecithin, oleic acid, citric acid, polyethylene glycol, and hydrochloric acid.11,32,67,68 These compounds may be used as cosolvents, surfactants, or suspending agents and they can influence the stability and drug delivery attributes of MDIs by changing formulation density, affecting formulation atomization, changing the emitted droplet size, and evaporation that would influence the residual particles. 69 The choice of the excipients used may depend upon the drug, propellant, and compatibility with the CCS. Excipient change is generally triggered by change in the source, which may be due to the applicants’ desire to have a second source of the excipient as part of the risk mitigation strategy, or because the excipient from the original source is no longer available, or the original supplier has withdrawn from the market. 70 Among the several SUPAC guidance issued earlier, the SUPAC SS guidance 4 addresses changes in excipient in terms of “Change in a supplier of a structure forming excipient that is primarily a single chemical entity (purity >95%) or change in a supplier or technical grade of any other excipient.” Changes in sources of propellants may affect the excipient quality, and its impact on formulation and drug delivery attributes of MDIs may vary with the level of change. Development strategies for complex products based on QBD usually involve the inclusion of a second source into design of experiments to establish that the process CQAs and the product QTPP are not affected or can be accommodated within a modified design spaces.
Table 3 does not include examples of excipient changes that can be classified as Level 1, 2, and 3 modifications. The existing SUPAC IR 2 and MR 3 guidance developed in the absence of the QBD concepts consider the excipient change as part of the “Components and Composition.” In the IR guidance “Level 1 changes are those that are unlikely to have any detectable impact on formulation quality and performance.” The examples include changes in the excipient expressed % w/w of total formulation. Level 2 changes are those that could have a significant impact on formulation quality and performance, for example, solubility and permeability. Level 3 changes which include both qualitative and quantitative changes in excipient(s) are those that are likely to have a significant impact on formulation quality and performance. Testing requirements for Levels 1, 2 and 3 changes include comparative dissolution without or with in vivo pharmacokinetic study. The in vivo study requirement can be waived in the presence of established in vitro-in vivo correlation (IVIVC). Based on the FDA guidelines, the excipient functionality is an important consideration in the determination of testing requirements for SUPAC MR. 3 The excipients are categorized as “nonrelease controlling” and “release controlling” agents. The testing requirements to support changes in the nonrelease controlling excipients are essentially similar to those stated for SUPAC IR. However, testing requirements escalate for changes in the release controlling excipients, with pharmacokinetic evaluations beginning at Level 2.
The existing FDA SUPAC guidances consider up to 5% w/w cumulative change in excipients as the allowable limit that can be supported by in vitro dissolution/release testing. Although no such limits are available for the OIDPs, the FDA recommendations for generic versions of complex, locally acting products provide for excipient amount/concentration deviation within 5% of the formulations of the applicable RLDs. Exception to this requirement is the recent development of a generic version of the Symbicort® HFA MDI. 71 Nonetheless, this product was developed for the 505(J) submission, and did not represent a postapproval change in an approved product. The applicable regulatory requirements included application of all components of the FDA-recommended “weight of evidence” approach 72 and additional in vitro testing to support deviations from the recommended qualitative (Q1) and quantitative (Q2) sameness of formulations.
In the authors’ opinion, testing requirements for postapproval changes in excipient(s) used in MDIs would depend upon the nature of change and the extent of deviation from the data submitted in the original application or relevant information available in the applicable DMFs. Changes within the design spaces (or approved ranges) would be considered minimal risk deviations. However, even minor changes in excipients would warrant testing consistent with the applicable compendial and regulatory considerations. 11
Device
The MDI CCS consists of metering valve, canister, and actuator. Postapproval changes may happen in any of the three components and, therefore, warrant separate examinations with respect to SUPAC.
Metering valves
Metering valves (noncontinuous) constitute the cardinal component of MDI as it determines the amount of drug delivered upon each actuation as well as consistency in drug delivery over multiple actuations during the approved use life of the product. Thus, proper and consistent functioning of metering valves is crucial to releasing a consistent amount of the formulation at each actuation, and maintaining uniformity in the amount of bulk formulation delivered over all labeled number of actuations. MDI valves consist of elastomeric components, a metal spring, a metal ferrule, and the remaining components that can be either metal or molded plastic. A discussion of mechanical operation of the metering valve and role of each component in MDI functioning and drug delivery would be redundant in view of abundant availability of the relevant information.73–75 Instead, we herein focus on the changes that can happen in the MDI valves. Based on the authors’ experience, changes in the MDI valves during product development or postapproval are limited to molded plastic components and gaskets. The MDI valve includes a ferrule gasket, also known as neck gasket, and a metering gasket. The ferrule gasket provides a seal between the canister and the valve, preventing leakage of propellant from the canister and ingress of moisture into the formulation. 71 The metering gasket isolates the metering chamber from the container holding the bulk formulation. 76
The MDI gaskets may comprise suitable elastomeric material such as low-density polyethylene, chlorobutyl, black and white butadiene-acrylonitrile rubbers, butyl rubber and neoprene, cyclic-olefin-copolymer, ethylene propylene diene monomer (EPDM), nitrile, or chloroprene rubbers.71,77 Changes in gaskets may include elastomers and/or the manner the gaskets may be treated/processed.78–80 Elastomeric and plastic components of the MDIs are capable of leaching compounds into the formulation due to the close contact. Thus, they are considered the major source of extractables. Rubber seals can swell because of solubility with the propellant. 81 Thus, changes in, or treatment of, gaskets can affect the leak rate, moisture ingress, as well as extractables/leachables, 82 influencing both effectiveness and safety of the products. Impact of each change will depend upon both the nature and extent of change. Unless any of the changes made are qualified during product development and approval, implementation of the changes would warrant Prior Approval Supplement (PAS), supported by testing to include Delivered Dose Uniformity (DDU), APSD, and extractable/leachable studies (where applicable). The molded plastic components within the MDI valve (valve stem and metering chamber) that play a crucial role in metering the formulation are generally not changed. The changes are usually driven by supply chain or business needs that may be unavoidable. However, any change in these plastic components will need to be assessed just like the above discussed changes in elastomers for their impact on delivered dose uniformity, extractables/leachables. One thing to note is that while the DMF holder or applicant may not want to change critical device subassembly components, the manufacturers of these pharmaceutical-grade metering valves are dependent upon the conglomerate of plastic, metal, and elastomer manufacturers for whom the pharmaceutical valve components may not be a major business revenue. Hence, decisions by these manufacturers eventually will impact the business and regulatory assessments of both the MDI valve manufacturers and the applicants.
Canister
Based on the authors’ experience, postapproval changes in canister are very rare. MDI canisters are made from aluminum or steel, and they are available as plain, anodized, or with coating of the internal surface to prevent drug adsorption.83–87 Thus, changes in material of construction (MOC) of canisters would have potential to affect formulation stability, drug delivery, and extractable/leachable profiles—all implicated in sustained safety and efficacy of the approved products. Consequently, changes in MDI canisters would require determination of equivalence between the approved and the modified canister with respect to leachable quality and quantity, DDU, and APSD. Lack of equivalence in leachable profiles would require discussion with relevant regulators. Qualitative differences in leachables might warrant toxicology evaluations. Changes in DDU and APSD within the acceptable boundaries may not evoke regulatory actions, while data outside the established design spaces would require regulatory consultation and/or additional in vitro/in vivo testing.
In addition, a change in the canister can be driven by request for physician samples of the product, which carry reduced number of doses. While this may lead to a smaller size of canister and/or reduction in the formulation fill volume, the impact of the new development work will be similar to the above assessment on DDU, APSD, extractables/leachables, and stability over the product shelf-life.
Actuators
The MDI container carrying the formulation and fitted with a valve is placed in a plastic actuator, which, upon actuation, converts formulation ballistically exiting the valve into a plume of fine droplets/particles appropriate for drug delivery to the patients’ lungs. Both the MOC and design of the actuator are important for desired drug delivery. The actuator plays a key participatory role in the formulation atomization, plume formation,88–90 and plume dissipation. 91 MDI aerosols are electrically charged by triboelectrification as formulation rapidly travels through the valve stem and actuator.92–94 Certain MOCs may influence the electrostatic charge profiles from MDI and affect APSD. 95 The MOCs, additives, and colorants are also important considerations with respect to extractable/leachable profiles of the MDIs. 80 The design and dimensions of the actuator critical parts, including sump, nozzle, orifice, and mouthpiece, also affect plume quality, 96 plume geometry, 97 and APSD,98–100 influencing lung deposition.
Thus, any change in the actuator MOC and design may affect both the safety and efficacy of drug products. In the authors’ experience, the actuator design and dimensions are frozen early in the development of innovator MDIs, and they remain essentially the same in generic drugs to meet the FDA requirements for device design and the relevant human factors101–103 appropriate for patient use of the device. Changes in actuators other than design and dimensions may originate from suppliers of MOC or the actuators. Applicants who intend to use more than one source of actuators would generally qualify the suppliers during product development and submit the qualifying CMC/Toxicology data in the application. Effect of any change beyond the submitted information and testing to support such change would be determined case-by-case based on the specific nature of the change.
Dose counters
MDI formulations are usually packed in opaque containers (aluminum or steel) which make it difficult for the patient to determine when to stop using the product, as the approved MDIs usually carry overfill to deliver beyond the labeled number of inhalation, 104 however, with no guarantee of sustained delivery beyond the labeled number of doses. The current agency guidelines also allow overfill, however, with justification needed to maintain the performance of the MDI throughout the labeled number of applicable actuations. 11
All CFC- and certain HFA-based MDIs were approved without dose counting mechanisms. Thus, the allowance for overfilling MDI formulations was deemed necessary to ensure the dosing consistency of each spray. 105 However, the FDA acknowledged that MDI used beyond the recommended number of doses might appear to be delivering a therapeutic spray, when it may not be. Therefore, the agency introduced a landmark decision to integrate dose counters in MDIs. 105 Its guidance requires evidence specifically for avoiding undercounting that could result in patients assuming they have medication left in their MDI when, actually, they may not.
Dose counter designs are varied. They may be mounted on top of the canister (top mounted) or incorporated within the actuator itself (actuator incorporated). While both designs have been implemented successfully, each design will need its independent assessment on the impact on the drug product CQAs highlighted above. In addition, the impact of the labeling, ease of use, and human factor assessments are necessary for consideration by the applicant such that the patient can use the product safely without a significant burden and confusion. If the dose counter includes electronics or digital display, additional requirements and regulatory expectations must be met.
Dry Powder Inhalers
DPIs rank second to MDIs in terms of number of inhalers used. 106 Compared with the MDIs, DPIs are environment friendly 107 as their carbon footprint per actuation is one-third or less.108,109 Although both MDIs and DPIs deliver the labeled number of doses of aerosolized drugs containing particles suitable for inhalation, the mechanisms of drug delivery from MDIs and DPIs are distinctly different leading to different inhalation instructions for product use by the patient. Inhalation of the MDI aerosol calls for slow and deep breath because the formulation release and its atomization and aerosolization do not depend upon the patient’s inhalation. Instead, these events are driven by energy imparted by the propellant. However, DPIs, which contain drugs in powder form, depend upon the patients’ inspiratory effort for the powder fluidization, entrainment, deagglomeration, and aerosolization (Fig. 1). Inhalation instructions for DPIs recommend quick and deep breath to assert inspiratory force required to activate drug release and pulmonary delivery. The patients’ inspiratory effort for achieving the flow rate required to produce pressure drop that triggers powder entrainment and affects drug release may vary with DPIs, as devices of approved DPIs exhibit different degrees of internal resistance to air flow. 110 The inspiratory effort for a given DPI may also vary among the target populations 111 and with disease.112,113
Distinction between sources of energy for drug release and inhalation from metered dose inhalers (MDIs) and dry powder inhalers.
A detailed discussion of the variety of drugs, formulations, and devices used in the approved DPIs and the applicable multitude of interactions and mechanisms is beyond the scope of this article. Therefore, instead of digressing into details that are found in a number of comprehensive reviews published to date, this article dwells upon the DPI attributes relevant to SUPAC. The QTPPs applicable to DPIs are essentially similar to those of the MDIs due to the commonality in route of administration, target site (lung), mechanism of drug deposition and distribution within the target site, approved clinical indications, and indices of effectiveness and safety. Principal distinctions from the MDI PQAs listed in Table 1 are fill weight (in place of shot weight) and foreign particulate matter. 114 However, scientific deliberation for DPIs regarding SUPAC warrants special considerations for the drug substances, excipient(s), and devices due to the distinctions between the MDIs and DPIs with respect to influence of properties of powder constituents and operating mechanisms of devices, which collectively influence the CQAs relevant to the QTPPs.
The approved DPIs are marketed as single-dose capsule or blister cartridges packed together with device, fully integrated drug–device units with formulations contained in premetered unit doses, or powder reservoirs from where the devices meter each dose. 115 Although these products have different operating mechanisms, the fundamental operating principle is the same; they depend on the patient’s inspiratory effort to activate drug delivery. The patient’s ability to generate sufficient flow for effective DPI use is controlled by negative pressure generated by the patient’s inspiratory flow within the device, which is influenced by the internal resistance of the device. 116 The required level of inspiratory effort varies with product as well as disease, 117 because of the variability in the internal resistance of approved DPIs,118,119 which can influence peak flow rates.118,120 Accordingly, both the quantity of drug delivered and its particle size distribution may vary with the device, patient population, and lung caliber.121,122
Drug delivery from DPIs is also influenced by quality attributes of the powder formulations. Most approved DPI formulations consist of the drug substance(s), carrier, and additives (where applicable). Quality attributes of these entities contribute to the powder formulation CQAs, which affect the PQAs relevant to drug delivery and formulation stability. Thus, the discussion below considers the various components and the relevant CQAs listed in Table 4 in terms of possible changes in DPIs, which might occur postapproval. Analytical testing or other studies, which might be required to support the changes and the applicable regulatory pathways, are summarized in Table 5.
Dry Powder Inhaler Quality Attributes Related to Postapproval Changes
Examples of Postapproval Changes in Dry Powder Inhalers, with the Relevant Testing and Regulatory Considerations
With appropriateness and adequacy by seeking timely advice from the relevant regulatory agency.
Regulatory compliant product development, including use of adequately validated methods using applicable current GLP and cGMP.
IVIVC, in vitro-in vivo correlation.
Drug substances
There is commonality of quality attributes of drug substances relevant to drug delivery and stability. As stated for the MDIs, the aerodynamic particle size (1–5 µM) and polydispersity of the drug substance particles constitute the principal determinants of pulmonary deposition. Production of drug substances in that range requires reduction in the size of previously formed larger sized crystalline material, and the common method for particle reduction is micronization. This mechanical comminution may affect a variety of quality attributes, including particle size distribution, crystalline/amorphous content, rugosity, flow properties, electrostatic change, cohesive/adhesive characteristics, and dissolution.49,50,123,124 A change in any of these quality attributes, or a combination thereof, may affect the stability of drug substance. In addition, due to the complexity of interaction with excipient(s) in the powder formulation, it may influence the stability and downstream performance of DPIs.125,126 Physical stability postmicronization can be enhanced by conditioning for structural relaxation through charge dissipation, recrystallization affecting interfacial interactions.48,127,128
Excipients
Cohesiveness among micronized drug particles results in poor aerosolization due to formation of agglomerates. Carriers with larger particle size in the range of 48–192 µm may be introduced to enhance drug particle flowability, ease of handling, and improve dosing accuracy.129,130 The carriers commonly are coarse particles that would be swallowed after impact with the upper respiratory tract (throat). Thus, the formulation of most approved DPIs contains a binary blend of micronized drug(s) and larger carrier particles, 131 or free flowing agglomerates manufactured as stabilized microcrystalline arrays of drug and excipients that allow ease in handling and accurate dose metering.132,133 The carrier constitutes bulk of the drug-carrier blends. Therefore, performance of DPIs is influenced by the carrier particle size; reduction in particle size may enhance the delivered fine particle mass of the drug.134,135 In addition to establishment of optimum particle size, considerations of the physical properties of carrier particles, including their shape, surface roughness, density, and geometric diameter, are also relevant.136,137
Several excipients, including lactose, mannitol, sorbitol, erythritol, anhydrous glucose, trehalose, magnesium stearate, lipids such as Dipalmitoylphophatidylcholine (DPPC)/Dipalmatioylphosphatidylglycerol (DPPG), and fumaryl diketopiperazine (FDKP), have been studied for use in DPI formulations, and some found unsuitable as carriers.138–140 In addition, studies using other natural biodegradable polymers, including DPPC/DPPG, Poly(lactic-co-glycolic) acid (PLGA), and chitosan, have been reported to target pulmonary retention and control released pulmonary drug delivery. 141
Among the various excipients, lactose is the most common and frequently used carrier in DPI formulations. It is available in various inhalation grades, sizes, and with different physicochemical properties. DPI formulations generally use a mixture of coarse and fine lactose for optimum drug delivery. 142 Addition of lactose fines in binary mixture containing micronized API may improve fine particle mass143,144 attributable to the higher surface roughness, amorphicity, and surface energy. 145 However, it may have opposite effect with certain formulations.146,147 Nonetheless, incorporation of fines requires careful evaluation, as the fines in the aerosolized dose may agglomerate with drug particles148,149 and deposit in the lung with potential to cause bronchoconstriction 150 and increase in bronchial hyperresponsiveness. 151
Lung deposition from the carrier-based DPIs is limited to ∼30% due to the cohesive–adhesive balances sufficiently strong to hold particles together during the manufacturing process, storage, and fluidization, but weak enough to free the API particles upon aerosolization. 152 Limited efficiency of such DPIs has proven to be a major hurdle in the delivery of high doses.153–155 To overcome this limitation, particle engineers have focused on the development of carrier-free DPI formulations, 156 which contain drug(s) embedded in the excipient particles. Among the available techniques for producing micronized particles for inhalation,57,115,157 spray-drying has been used in manufacturing respirable pharmaceutical powders in approved DPIs. 158 It demonstrates flexibility to processing both small molecules and biotherapeutics, or even combinations thereof, 159 and offers the advantage of producing particles with well-controlled reproducible physicochemical properties by adjustment of process parameters.160,161 For manufacturing of therapeutic powders by spray-drying, drug substances and excipients are codissolved in a volatile solvent and then atomized into droplets that are sprayed into a drying chamber. The solvent is rapidly removed by heated drying gas resulting in a dried powder that is collected via cyclone.162–164 Production of pharmaceutical powders using spray-drying extends beyond solutions to include emulsions 165 and suspensions. 166
The insulin DPI Afrezza® uses Technospheres®, which are 2–5 μm microspheres formed by the self-assembly of crystals of FDKP.167,168 Recombinant human insulin is encapsulated during precipitation of FDKP solution that produces microspheres. 169 Technosphere particles carry insulin into the alveoli where the particles dissolve. Both the insulin and the FDKP are absorbed across the alveolar walls independent of each other. 170
Formulation manufacturing
Drugs formulated in dry solid state are generally more stable than liquid formulations developed for inhalation.124,130,154,171 As briefly discussed above, both stability and performance of the dry powder formulations are influenced by the physicochemical properties of each component in the powder blend. However, during manufacturing, the dynamics of interactions among these ingredients also influence formulation attributes relevant to powder handling during manufacturing, primary packaging, and quality attributes related to safety and efficacy. Varied particle engineering methods, operation parameters, and storage conditions may affect stability of powders and their aerosolization.154,158 Interactions between the drugs and the excipients during mixing, blending, and the manufacturing process may introduce changes in the formulation, which might affect both performance and stability of the product. Thus, with respect to SUPAC considerations, it is also important to understand the effects of the various production methods that exert mechanical and thermal stresses, which can influence solid-state properties and physical stability of the DPI powders.
Particle sizes of drug(s) and excipient(s) in the conventional binary formulation are produced by milling, which introduces surface abrasions, amorphous content, and electrostatic charge. The resulting active sites on both lactose and drug(s) contribute to cohesive and adhesive forces, which affect formulation performance.172–176 Masking of these sites by “force” control excipients facilitates dispersions and improves aerosolization.177–179 In addition, the “force” control masking by excipients may also add to uniformity in quality and performance by rendering the surface chemistry near homogenous. Magnesium stearate is one such excipient that has been used in several DPIs approved in the United States and European Union.180–182 Its addition to lactose carrier particles before blending with micronized API particles reduces the adhesive forces between the lactose carrier particles and micronized API particles and improves aerosolization performance.141,183 Magnesium stearate also contributes to enhancing formulation performance by mechanical coating of drug substances via cojet milling.184,185 Addition of 2%–5% magnesium stearate is deemed sufficient for maximum improvement of the aerosolization performance of cojet milled formulations.
When two or more materials with different physical, chemical, and dielectric properties are combined, contacts between these particles and the same particles with metal equipment surfaces during pharmaceutical powder manufacturing trigger multiple physiochemical alterations generating contact charging or triboelectrification.186–188 Spray-drying may also produce particles with relatively high levels of electrical charge as the solutions prepared for drying are aerosolized into small droplets and dried in a hot-air cyclone.189,190 Charging of particle through triboelectrification may also occur during fluidization of the powder bed through the inhaler device and dispersion 191 and the level of charge may depend upon the energy input from the inspiratory force. 192
Electrostatic charge can influence drug delivery by causing aggregation and impeding fluidization, thereby reducing pulmonary bioavailability due to drug retention in the DPI device as well as increased deposition in the oropharyngeal deposition—even with the spray-dried formulations. 135 Both the formulation and device can be electrically charged, 193 and the electrostatic profiles of drugs before and after aerosolization may be different. The charge on aerosolized powder may be sum of the charge before fluidization and the charge gained during aerosolization, with the latter being the greatest augmentation. 194
High energy detected in freshly blended powders may be reduced by laagering, and conditioning at high humidity and temperature. Rates of charge decay from particle surfaces may depend on the relaxation time,195–197 humidity levels,198,199 and temperature, or a combination thereof. 200 In addition, composition of primary packaging may add to complexity in drug delivery affected by electrostatic charge. This is particularly relevant to DPI formulations packaged as unit doses in capsules made up of hard gelatin or hydroxypropyl methylcellulose (HPMC). 201 Tribocharging of capsules intended for dry powder inhalation can be related to their inherent chemical composition, manufacturing process, and environmental humidity. 202 Lubrication of these capsules to reduce electrostatic charge may impact respirable fraction of the drug, and the impact may be different for the gelatin and HPMC capsules.203,204
Devices
Upon inhalation from DPIs, airflow through the device creates shear forces and airflow turbulence, which break up the compacted drug powder and transport the inhalable portion of the dispersed formulation into the lung. 205 Thus, the level of deposition into the lungs is determined by the patient’s inspiratory effort and attributes of devices, including shape of the mouthpiece, air flow, and flow resistance.131,206 The latter two vary with the available devices,207,208 patients’ age, and disease indications.120,209,210 Device geometry and dimensions influence the airflow resistance of the device, which is positively correlated to the turbulence generated within the device. 211
DPI devices consist of drug compartment(s), air flow passages, dispersion grills, mouthpieces, dose counters, and operating components made from plastics. The powder formulation comes in contact with plastic as powder bed before inhalation and as deagglomerating mixture during movement through the device upon inhalation. Static charges on the plastics also have the ability to attract the drug formulation and therefore potentially reduce the amount of drug delivered. 212 Thus, electrostatic charge on the plastic components in the airflow path within the DPI devices can have a strong impact on material loss during manufacturing of the product, loading, and discharging upon actuation of the inhaler.213,214 The highly charged particles can deposit on the surface of the inhaler device by electrical precipitation, resulting in reduced bioavailability, which may result from a high amount of drug being retained by the DPI device.135,191
The DPI efficacy, safety, and stability are an outcome of a combination of the physicochemical properties of drugs and excipients and their interactions in the formulation, the powder manufacturing process, environmental variables during manufacturing, and devices. 215 Device design and operating mechanisms are relevant to effective use of DPIs by the patient populations. Device design takes into account necessary human factor assessment relevant to the proper use of the products. Changes in critical attributes of the device not only affect the DPI performance with respect to drug delivery, but also the patient use. Thus, robustness of device and patient usability would be important considerations in any SUPAC relevant to devices.11,216,217
Soft Mist Inhalers
Innovation in respiratory drug delivery led to the development of a variety of nebulizers, MDIs, DPIs, and SMIs. The FDA also categorizes the latter as inhalation sprays. 218 SMIs overcame limitations of need for electrical energy and delivery efficiency with nebulizers, ballistic effect and environmental concerns of MDIs, and the need for inspiratory efforts above a certain threshold for most DPIs. Spray velocity and duration are critical aerosol parameters that influence lung deposition. The aerosol sprays released from SMI move with lower velocity, have longer duration than the MDI plumes, and carry greater fraction of fine particles compared with most MDIs and DPIs.219,220 The characteristic slow velocity mist from SMIs evades high oropharyngeal deposition, yields higher lung deposition, and excludes the need for the press-breathe synchronization necessary for most MDI devices.221,222
Currently, Respimat® is the only SMI platform marketed in the United States for Boehringer Pharmaceuticals’ four products—Combivent®, 223 Spiriva®, 224 Stiolto™, 225 and Striverdi®. 226 Its dosage form is designated as “spray, metered: inhalation,” unlike “aerosol, metered: inhalation” designation used for the MDIs. Respimat® mixes the concepts of the functional mechanism of nebulizers with the advantage of having a portable multidose inhaler. 227 Similar to all inhalers, its efficacy relates to the portion of the drug reaching the lungs and APSD of the emitted spray, which determines regional deposition. However, in view of the SUPAC, the functionality of the SMIs warrants considerations of other performance indicators, formulation and the relevant physicochemical properties, and spray attributes, including pattern, geometry, velocity, and duration.
Among the numerous characteristics of the drug substances relevant to the OIDPs, 228 significance of certain physicochemical considerations related to particle size, shape, amorphicity, and surface characteristics of the drug substance may be irrelevant to the performance of drugs formulated as aqueous solutions. Nonetheless, manufacturing and process controls affecting chemical attributes of the drug and related substances would be relevant to SUPAC.
The physicochemical properties of the aqueous formulations for aerosolization also influence plume formation, plume speed, duration, and APSD. Respimat formulations in the United States and European Union are reported to be aqueous- or ethanol-water-based.229,230 The fine particle mass produced by the Respimat® SMI was different for an aqueous fenoterol solution and ethanol solution of flunisolide. The difference was attributed to lower velocity recorded for ethanolic solution spray compared with the aqueous, resulting in longer duration of dose release. 231 Nonetheless, all Respimat formulations approved in the United States are sterile aqueous solutions containing the specific drug(s) and the excipients edetate disodium, benzalkonium chloride, with the exception of hydrochloric acid replacement with anhydrous citric acid only in Striverdi®.
A variety of quality attributes related to formulation and device performance are relevant to the safe and effective use of SMIs. 232 Among these, the significance of characterization and control of related substances and leachable for the drug product safety is well established. In addition, physical properties such as surface tension, viscosity, and ionic strength can influence droplet size distribution and speed of aqueous aerosols.233–235 Changes in viscosity affect droplet size and fine particle fraction.236,237 Output of the spray and accumulation of droplets in the device may also be affected by surface tension.238,239 Furthermore, control of solution pH is relevant to local safety after inhalation, as low pH can induce coughing and irritation in the patient’s lung.240,241
Device performance of Respimat-like products is based on the amount of drug per actuation, particle size distribution of the spray, plume characteristic determinants of geometry and pattern of the spray, plume speed, and its duration. The FDA frequently publishes brief statements regarding these tests in its product-specific guidances.242,243 Similar to the MDI and DPI devices, human factor considerations are also applicable to SMIs.244–246
The DPI and MDI sections include brief mentions of studies that may be required to support SUPAC as well as the applicable regulatory pathways dependent upon the extent of change. Similar discussion for the SMIs would be a repletion of some of the same avowals. However, the foregoing discussion should be helpful and serve as a template in the formation of a testing plan for SUPAC in SMIs.
Manufacturing Site Change
Manufacturing site changes include changes in location of the site of manufacture, packaging operations, and/or analytical testing laboratory in the company-owned and/or contract manufacturing facilities. They may or may not include any scale-up changes, changes in manufacturing (including process and/or equipment), or changes in components or composition. New manufacturing locations are expected to be compliant with the current GMP and proven satisfactory upon regulatory inspection.
As mentioned above for the other SUPAC considerations, changes in manufacturing sites can also be classified at three levels. Likewise, the testing to support the change and the regulatory pathway will vary with the level of the change (see Table 6).
Testing and Regulatory Considerations Relevant to Changes in Manufacturing Sites
Changes consist of site changes within a single facility where the same equipment, standard operating procedures (SOPs), environmental conditions (e.g., temperature and humidity) and controls, and personnel common to both manufacturing sites are used and where no changes are made to the executed batch records, except for administrative information and the location of the facility.
Same as (1), except for administrative information and the location of the facility.
The same equipment, SOPs, environmental conditions, and controls should be used in the manufacturing process at the new site, and no changes may be made to the executed batch records except for administrative information, location, and language translation, if necessary.
CBE, changes being effected.
In Vitro and In Vivo Testing to Support SUPAC
SUPAC changes in drug products require studies determinant of the effect of the changes on product performance reflective of drug delivery and quality attributes relevant to the drug product safety and efficacy. These studies are conducted to show equivalence between the pre- and the postchange versions if the change occurs during development or postapproval of an originator product. However, for the follow-on (generic) versions of the OIDPs, the FDA would generally require demonstration of equivalence between the postchange version of the Test product and the relevant RLD.
Studies to support SUPAC may include chemical characterizations, evaluations of the product CQAs, performance testing relevant to drug delivery, and/or determination of equivalence based on human studies. In the absence of the publicly known regulatory precedents for approval of SUPAC in OIDPs, it would be prudent to determine testing requirements based on the nature of the change and taking into consideration complexity of the products that are drug–device combinations. Changes in drug substance synthesis and sources of intermediates would warrant relevant characterization studies, if the proposed changes are not supported by the information submitted in the relevant DMFs. Similarly, changes in excipients within the scope supported by the DMFs may not need additional testing. Alterations in these basic ingredients of formulations would require characterizations appropriate to support the changes, and it may include leachable studies and determination of related substances/impurities at batch release and during stability testing to establish sustained safety of the product.
Changes in formulation and/or device may affect product performance, which would require comparative in vitro drug delivery studies. These studies vary with the OIDP class; for MDIs, the tests include determination of single-actuation content (SAC), APSD, priming/repriming where applicable, and spray pattern and plume geometry. For DPIs, the SAC and APSD studies might require determinations at multiple flow rates, which generally are three including the one stated in the product labeling, and other two representing 50% and 150% of the labeled flow rate. For example, labeled flow rate for the Advair® DPI is 60 L/min, the flow rates recommended for in vitro testing are 30, 60, and 90 L/min. 247 The revised products may be required to meet in vitro equivalence at all three flow rates. SAC and APSD testing are common to all OIDPs. In vitro testing to support changes in SMIs would also require comparative studies of plume speed and plume duration.
In vitro testing for SAC and APSD determinations is generally based on compendial methods using the United States Pharmacopeia (USP) throat and flow kinetics not reflective of the human mouth throat and inhalation patterns. Thus, in vitro testing based on compendial recommendations may not be clinically relevant. Consequently, equivalence of the OIDPs before and after the proposed change based solely on in vitro testing may be deemed inadequate to support the change, particularly in the absence of IVIVC establishment during product development. To address such issues, the FDA has been encouraging incorporation of clinically relevant in vitro testing that uses anatomically relevant mouth-throats (MTs) 72 and employ flow rates representative of the target populations and/or disease severity. Small, medium, and large MTs may represent MT variations among pediatric patients and adults, whereas the week, medium, and strong flow rate profiles may be representative of mild, moderate, and severe levels of the disease.
In vitro testing to support approval of changes in OIDP generally requires three batches of the products before and after change, with 10 inhalers from each lot to be evaluated at three flow rates using the USP throat. However, for clinically relevant testing, the single USP throat is replaced with three (small, medium, and large) MTs, thereby increasing the required effort by three times. Furthermore, in vitro performance testing for SAC and APSD may be further multiplied by the number of the OIDP strengths which, for example, are three for the Advair® DPI. All this contributes to huge testing burden. However, it is noteworthy in this regard that the FDA may consider bracketing to reduce total testing. 72 Nonetheless, before its application, the nature and extent of bracketing should be cleared with the agency through product development meetings.
Data from clinically relevant in vitro studies provide valuable input for in silico determination of total lung deposition and within-lung distribution.248,249 Therefore, equivalence of the revised OIDPs for SAC and APSD based on clinically relevant in vitro testing and the lung deposition derived from the in vitro data may be sufficient to demonstrate sustained effectiveness of the product. Failure in meeting equivalence criteria for one or few of many in vitro comparisons should be determined case-by-case with concurrence of the agency, as the magnitude of failure in meeting equivalence would trigger in vivo testing in humans, which includes pharmacokinetic and clinical endpoint studies (CEPs). Of these, CEPs for OIDPs generally lack the sensitivity required to discriminate between potentially inequivalent products. However, pharmacokinetic studies hold the best promise to distinguish between products that may be different but found comparable in CEPs250–252 and pharmacodynamic testing. 253 Interestingly, pharmacokinetics distinguished between products that were found equivalent based on in vitro testing.250,251 It is noteworthy that for demonstration of in vivo bioequivalence (BE) of generic SMIs, the FDA requirement may be limited to comparative bioavailability studies.242,243 Based on the latest product-specific guidance issued by the agency, it provides options for determination of in vivo BE based on pharmacokinetic evaluations, which include recommendations for determination of relative bioavailability both without and with blockage of drug absorption from the gastrointestinal tract using activated charcoal. 72 The latter study design has been widely recognized for its suitability for determination of lung deposition of inhaled drugs,254–256 and it has been recommended since 2009 to establish lung deposition to support regulatory approval of multisource OIDPs in the European Union. 257 In the authors’ opinion SUPAC in OIDPs can be addressed based on in vitro or a combination of in vitro and in vivo testing discussed above, without pharmacodynamic evaluations or CEPs. However, this proposal may not be adequate to support changes with a multitude of ramifications. One such example is the replacement of the hydrofluoroalkane propellants in the currently marketed MDIs with new propellants that exhibit low global warming potential. Although this is an excipient change that, logically, can be weighed in with the scientific considerations discussed herein, the propellant substitution has ramifications for interactions with drug substances, formulations of new products will be qualitatively different from the existing products, and the change may also require alterations in devices—all that may yield products for which determination of safety and efficacy may require longer term clinical evaluations.
Introduction of dose counters to MDIs was a major postapproval change. The FDA solicited evidence to support the dose counter reliability through comparative in vitro testing simulating use and potential abuse, and clinical evaluations preferably in phase 3 trials. For introduction of dose counters to existing products, the agency required evidence for the dose counter functionality, reliability, and accuracy from patient in use studies conducted in target population(s).258,259 As stated above, postapproval changes in dose counters are not expected with the exception of cessation of supply or intention to change the counting format (e.g., where applicable, replacing a dose indicator with a counter that counts each actuation). In such cases, the stated in vitro and in vivo testing, and applicable human factor studies may be needed to support the change. Such changes would require approval through PAS submissions.
The DPI’s efficacy, safety, and stability are an outcome of a combination of physicochemical properties of drugs and excipients and their interactions in the formulation, the powder manufacturing process, environmental variability during manufacturing, and devices. 215 Device design and operating mechanisms are relevant to the effective use of DPIs by the patient populations. Device designing takes into account human factors relevant to the proper use of the products. Changes in critical attributes of the device not only affect the DPI performance with respect to drug delivery but also the patient use. Thus, robustness of device and patient usability would be an important consideration in any SUPAC relevant to devices (FDA 2018).216,217
Scientific rationale for determination of studies to support SUPAC in MDIs and DPIs can also be utilized for studies relevant to changes in SMIs, with consideration of additional product-specific CQAs such as plume speed and plume duration. The foregoing discussion should be helpful and serve as a template in the formation of a testing plan for SUPAC in SMIs, if any. Similar to the MDI and DPI devices, human factor considerations are also applicable to SMIs.244–246
Finally, any discussion on changes that can affect the drug product efficacy and safety must also consider biocompatibility. From the OIDP perspective, ensuring biocompatibility is crucial to avoid adverse reactions or health risks associated with the materials used in the device, and it is an important consideration in their design, development, and approval. The International Organization for Standardization (ISO) recommended ISO 18562 testing as a requirement for MDIs. 260 In vitro cytotoxicity testing is relevant due to the prolonged contact of mouthpieces with users on a daily basis. Some of the currently approved DPIs, including Aerolizer®, Diskus®, Elpenhaler®, and Turbuhaler® when evaluated in a comprehensive study, were equivalently safe for long-term use of mouthpiece. 261
Conclusion
This article delineates scientific and regulatory implications of SUPAC in OIDPs, which are complex drug–device combination products marketed as MDIs, DPIs, and SMIs. The three product classes are distinctly different with respect to formulations and devices, yet approved for same indications in similar patient populations. In addition, these products are characterized by similar QTPPs relevant to the drug product’s safety and efficacy. The principal constituents of these products are also similar as they contain drug substance(s), formulation(s), and devices that are collectively relevant to pulmonary drug delivery. However, effects of change(s) in the same constituent(s) of products may vary among the three categories. Particle size and surface properties of the drug substance(s) may have a minimal effect on the aqueous formulations used in the SMIs, whereas their impact may be both qualitatively and quantitatively different on the manufacturing and performance of MDIs and DPIs. Similarly, changes in the inactive ingredients are likely to have different effects on physicochemical properties of the formulations in the MDIs, DPIs, and SMIs. Likewise, any changes in the CCSs would warrant product-specific scientific considerations in developing understanding of the effect of change(s) on the safety and efficacy of drug products.
Although the FDA has issued guidelines for SUPAC in solid oral and semisolid drug products, the agency has not made such recommendations for the OIDPs. The authors believe that studies to support changes in these products can be conceptualized by taking into consideration a variety of the FDA guidances for quality and product characterization related to drug substances, excipients, device constituents of combination products, and drug products, as well as in vitro testing and in vivo evaluations determinant of equivalence in in vitro performance, lung deposition, and clinical effects relevant to drug product safety and efficacy. SUPAC in the products’ constituents may be categorized into Levels 1, 2, and 3, and the change level would determine the extent of testing requirements and regulatory commitments required for implementation of the change. Level 1 deviations would represent alterations within the ranges of studies in product development and covered in the original application and supporting documents such as DMFs. Such deviations may be eligible for consideration as changes being effective without new testing.
Levels 2 and 3 changes may require CBE-30 notification or PAS approval for implementation of the changes in the drug products. The testing requirements to support such changes will depend upon the change and its complexity, as alteration in one constituent of the OIDP would affect other constituents. At minimum, it would require equivalence of physicochemical properties related to drug product performance and stability between the original product and the altered products. Absence of equivalence would indicate potential issues relevant to the safety and efficacy of the products, and it would require in vitro and/or in vivo determination to support the change. Rationalized drug product development based on the QBD concepts, including establishment of IVIVC, might limit the required testing to in vitro/in vivo evaluations.
Determination of the impact of change(s) and testing requirements would warrant case-by-case evaluations. Scientific complexities and regulatory guidelines briefly discussed herein might be helpful in developing a rational approach to accommodate change(s) in OIDPs. However, before implementation, the testing plan and the appropriateness of the regulatory pathways should be aligned with the regulatory agency(s).
Footnotes
Authors’ Contributions
G.J.P.S.: Conceptualization, literature review, and writing. S.P.P.: Writing.
Author Disclosure Statement
The authors have no conflict of interest.
Funding Information
No funds were received from any organization related to the effort invested in drafting this article.