Guidance Summary 121 - 130
Guidance 121 Summary - Assessment of Shipping Processes for Drug Products
Awareness of worst-case conditions, the potential for unexpected delays and product stability knowledge, for example, are among key inputs to understanding the potential for risk to product quality from shipping. Where the risk to product quality is significant, qualification of the chosen shipping process may be appropriate.
For more robust products (i.e., less environmentally sensitive, more stable products) where the risk assessment indicates that shipping does not pose significant risk to product quality, an shipping qualification study is not a value-added activity and the risk assessment is by itself sufficient documented information to establish that we have evaluated the shipping process for that product.
Knowledge of product stability is a key part of understanding the risk to product quality from the shipping process. Information about product stability can come from several sources, such as:
- Regulatory filing for a formulated DP;
- Routine, annual stability testing requirements
- Accelerated stability challenges, where the conditions used for accelerated stability testing may in some cases approximate expected worst-case limits of variability of environmental conditions approached during some phases of transit;
Environmental variations to which the product may be exposed include conditions at origin, destination, transportation hubs and throughout the transit route. Environmental profiles should be based on realistic expectations of transport conditions, developed using scientifically sound criteria. This may be done in various ways such as using review of historic data, review of published standards, or field-testing/monitoring of actual shipments including seasonal variations. Profiles should include anticipated extreme conditions that challenge the effectiveness of controlling temperature, exposure to moisture, prevention of oxidation, etc. as appropriate, with the packaging to be used.
Shipping conditions such as unforeseen transport events (such as delays), temporary storage in uncontrolled environments while awaiting the next stage of transportation, and variations in weather can expose product to conditions outside the long-term storage conditions established with the product registration.
Transportation conditions can pose several potential threats to product quality. Such as
- Temperature variation;
- Variable pressures, experienced by products shipped by air transport;
Some products require storage and transport under controlled temperature to maintain product quality. In general, use of opaque primary packaging protects susceptible products from damage due to light.
Guidance 122 Summary - Cold Chain Management of Biopharmaceutical Materials
Biopharmaceuticals, like other drugs, are used for the treatment, prevention or cure of disease inhumans. Biopharmaceuticals are of large molecular size and structural complexity and may include proteins, monoclonal antibodies, glycosaminoglycans, hormones, vaccines, oligonucleotides and PEGylated molecules.
Biopharmaceutical products are often defined by their manufacturing processes. Changes in the manufacturing process, equipment or facilities could result in changes to the biological product itself and potentially require additional clinical studies to demonstrate the product’s safety, identity, purity and potency. Biopharmaceuticals are further characterized by their high susceptibility to irreversible degradation and exceptionally high financial value per unit.
Temperature, agitation and exposure to light are among the conditions known to degrade protein and oligonucleotide based materials.
A risk assessment should be conducted that examine potential conditions under which the integrity of each biopharmaceutical materials is known to be compromised. Among the points to consider:
During transport by air, each take-off and landing may result in pressure changes that could potentially impact container integrity through expansion and contraction, as well as accelerated coolant loss due to increased pressure.
To a lesser degree, pressure changes must also be considered for ground transportation in specific geographical locations.
Photo stability studies conducted on some biopharmaceutical products have shown that aggregate formation is possible on exposure to light. Transparent packaging, especially for refrigerated materials, should be avoided due to potential light exposure in walk-in cold rooms.
The shipping and distribution processes for drug substances and drug products should be qualified for commercial products, a summary of which is required for regulatory marketing applications of biopharmaceuticals. It should be noted that transport temperature ranges may be wider than the labelled storage temperature range for any given product, however, data to cover the anticipated transport process (mode, duration, container) and qualification testing of the product after transport is expected.
Transport vehicles themselves may function as an active system (i.e. temperature controlled trailers). Proper setting of the temperature set point and loading of materials in a container or trailer is required to ensure that the temperature is properly controlled. Unless otherwise qualified, loads should not be placed against the walls of the transport vehicle to allow for proper air circulation within the cargo area and to ensure ambient outside temperature does not transfer directly to the load. Temperature is typically controlled by air circulation; as such air vents must not be blocked by the shipment materials.
Guidance 123 Summary - Stability Considerations for Planned or Unplanned API Process Changes
- Process scale-up
- Implementation of a revised process
- Implementation of a new rework procedure
- Change in packaging or packaging supplier
- Change in storage conditions
- Change to existing process equipment (i.e. repair, modification, replacement not like for like)
- Transfer of the process to a new or different site
- Change in critical raw material production process or supplier
Guidance 124 Summary - Clean Process - External Vial Capping Operations
“Clean Process” Capping Operations may be considered for GMP sites where aseptic processing operations as part of sterile medicinal product manufacture occur. The EU GMP Annex 1 includes the following statements:
“The container closure system for aseptically filled vials is not fully integral until the aluminium cap has been crimped into place on the stoppered vial. Crimping of the cap should therefore be performed as soon as possible after stopper insertion”.
(Paragraph 118)
“Vial capping can be undertaken as an aseptic process using sterilised caps or as a clean process outside the aseptic core. Where this latter approach is adopted, vials should be protected by Grade A conditions up to the point of leaving the aseptic processing area, and thereafter stoppered vials should be protected with a Grade A air supply until the cap has been crimped.” (Paragraph 120).
The air handler over the part of the capping operation where vials exit the aseptic area to the point of capping meet ISO 5 requirements for non-viable particulates.
Assessment of acceptable operation may be performed by routinely monitoring the physical parameters of the air handling system to supply Grade A quality air as outlined within EU GMP Annex 1.
Guidance 125 Summary - Use and Recovery of Solvents in API Manufacturing
Prerequisites for Solvent Recovery Process Validation include, and are not limited to, the following:
- Approved production Instruction-Records and applicable SOPs;
- Identification of all solvent recovery Critical Process Parameters;
- Qualification of direct impact equipment, facilities and systems, (including computerized systems). Verification of completion of equipment qualification should be included in the validation protocol; exceptions to this requirement should be approved by the Validation Committee (VC);
- Approved specifications for finished recovered solvent product and in-process testing;
- Validated test methods used to demonstrate quality requirements; and
- Personnel taking part in the validation work should be trained and qualified before carrying out such work, with training records documented.
Validated Solvent Recovery Processes that undergo major changes to incoming used solvent streams (e.g., those requiring a new solvent recovery process, or a stream that does not fit established criteria) require revalidation. In addition, major changes to equipment, facility, procedures or the solvent recovery process may require revalidation. Minor changes may not require revalidation but may require a documented, expanded test program or other formal evaluation.
Guidance 126 Establishing Reevaluation Intervals for API Intermediates
Introduction:
This document provides guidance for establishing re-evaluation intervals for API Intermediates that are stored dry or wet in drums or intermediate bulk containers (IBC). Wet intermediates include solvent wet, water wet, intermediates in solution (liquid) and intermediates in suspension. API Intermediates for Sale require stability studies and are outside the scope of this guidance document. Intermediates for Biological Products are also out of scope of this document.
Practice:
This document is intended to provide risk based guidance for the determination of re-evaluation intervals for API Intermediates. For API Intermediates that have a higher risk for degradation or for the proliferation of microbial organisms, hold time studies or microbiological proliferation studies can be used to support the determination of re-evaluation intervals.
- Dry intermediates or intermediates that are stored as oils that are considered stable through appropriate scientific judgment or literature search, through experience during development activities, or through consistent historical data gathered during routine manufacturing can use the “one year” default re-evaluation interval.
- Wet intermediates (Intermediates in solution, suspension, or wet cake) have a greater risk than dry intermediates for chemical degradation and/or microbial contamination. Microbiological concern is reduced if the material is wet with, dissolved in or suspended in an organic solvent as it is generally accepted that organic solvents impede the proliferation of organisms. Appendix I and II list risk assessment information for determining a re-evaluation period for wet intermediates relative to potential microbial proliferation.
Discussion & Recommendations
Intermediates that are stored wet have a greater potential for chemical degradation. If these wet intermediates are stored refrigerated or stored under nitrogen the potential chemical degradation process can be slowed. To support a storage time beyond 3 months, hold time studies should be considered.
Since analytical test methods for the evaluation of intermediates are typically not stability indicating the primary method of assessing chemical degradation is to process the intermediate forward, monitor subsequent processing, and test the final API for impurities. This activity can be performed retrospectively or prospectively.
See Appendix III for guidance on intermediate hold time studies to test the impact of any potential chemical degradation on the final API. Also intermediates that are stored wet have a greater potential for the proliferation of microbiological organisms. In addition to the risk of these microorganisms moving forward into the final API and subsequent Drug Product, there is the potential risk of by-products associated with microbial growth (endotoxins, exotoxins and other metabolites) also ending up in the final Drug Product. In assessing the microbial risk of storing wet intermediates there are two key risk components to consider.
The first component is severity which is determined based on the dosage form that will ultimately be manufactured from the API made from the wet intermediate. The second component is probability for microbial proliferation which is based on the manufacturing process and the storage conditions of the wet intermediate. The process for determining the risk band and ultimately a proposal for a re-evaluation interval relative to microbial proliferation is shown in Appendix I an II.
Risk Component One
The lowest severity factor “1” is for oral dry products or oral or topical non-aqueous liquid or semi-solid products. The severity factor is low for these products due to their typical low water activity which precludes further microbial proliferation. Severity factor “2” is for aqueous liquid or semi-solid oral and topical products, otic products, ophthalmic products, and inhalant products. The severity factor is intermediate because there is the potential for a higher water activity which could allow for microorganisms to grow. The final Severity factor “3” is for injectable products. This severity factor is high because this dosage form potentially presents the most risk to the patient as a result of microbial proliferation.
Guidance 127 Conversion to Animal Free or TSE Risk Free API Processing
Introduction
An “animal-free” process does not contain any raw materials, starting materials, components or agents derived from animals. A “TSE-risk-free” process does not contain any raw materials, starting materials, components or agents derived from animals known to be susceptible to Transmissible Spongiform Encephalopathy (TSE) agents.
When an API process or processing work centre is converted to animal-free or TSE-risk-free status, the following process elements should be assessed and shown to be consistent with these definitions: master and working cell banks or biologic seeds, process materials and recycle streams, equipment cleaning, process aides (e.g resins), process seeding and solvent recovery.
Practice:
For a process, process work center or process product to be considered “animal-free” or “TSE-risk-free” all elements of the process must be animal-free or TSE-risk-free according to the following definitions and requirements:
– Master and Working Cell Banks and Biologic Seeds – For master and working cell banks and biologic seeds to be animal-free or TSE-risk-free, those containing animal-derived materials should be recreated such that all animal-derived or all TSE-risk materials either are removed or are replaced with non-animal or non-TSE-risk counterparts.
Alternatively, the master and working cell banks and biologic seeds can be considered to have minimal TSE-risk if they are compliant with the European Medicine Agency’s “Note for guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (EMEA/410/01 Rev.2 – October 2003)” or its current equivalent. Compliant cell banks and seeds must have been created and described in a marketing authorization that was approved prior to 1 July 2000 for human health products or prior to 1 October 2000 for animal health products.
Alternatively, a marketing authorization holder can demonstrate compliance to the note for guidance by updating affected EU marketing authorizations individually with TSE-risk information or with an EP Certificate of Suitability for TSE compliance (TSE-CEP).
– Process Materials and Recycle Streams – All starting materials, raw materials, solvents, recycle streams, process aides, enzymes, cells or cell extracts, heels, tag ends, crystallization seeds, etc., must be defined to be of animal-free or TSE-risk free origin for an intermediate or API lot to be considered animal-free or TSE risk-free.
– Animal-free or TSE-risk-free process intermediate or API lots are considered different grades of material from their non-animal-free or non-TSE-risk-free counterparts and must be segregated and identified as animal-free or TSE-risk-free.
– Recycle streams such as mother liquors, filtrates, distillates, filter heels, or tag ends of lots must be animal-free to be added into an animal-free process. If an animal-containing material is added into an otherwise animal-free or TSE-risk-free process, the resulting lot must be considered animal-containing.
– Unless it is planned to retain a legacy animal-containing process in parallel with its animal-free or TSE-risk-free counterpart, legacy process recycle materials should be used up or destroyed upon conversion of a process to animal-free or TSE-risk-free status. If parallel manufacturing is planned, such legacy process materials must be clearly identified or segregated as not animal-free or not TSE-risk-free.
– Animal-free or TSE-risk-free lots may be reprocessed or reworked without jeopardizing their status so long as all elements of the reprocess or rework procedure meet the animal-free or TSE-risk-free criteria described in this bulletin. However, it is not possible to reprocess or rework a non-animal free lot or a non-TSE-risk-free lot to achieve animal-free or TSE-risk-free status.
– Equipment Cleaning – For an intermediate or API lot to be considered animal-free or TSE-risk-free, equipment product contact surfaces must be cleaned to prevent carryover of the previous product into the subsequent product. The equipment cleaning requirements and limits defined in the site guidelines should be followed.
– Cleaning procedures should be demonstrated to be effective.
– For multi-purpose equipment or work centers, the normal process changeover cleaning procedures define “clean.”
– For dedicated equipment or work centers, the normal cleaning requirements for cleaning between lots or between grades (e.g. Ag Grade to Rx Grade) define “clean.”
– Equipment, piping, tanks, etc. that are not product contact surfaces, but come in contact with animal-derived raw materials should be cleaned according to standard procedures prior to use in animal-free processing.
– A serial dilution approach may be used for bulk storage tanks, transfer lines and process systems that are difficult to clean and/or contain hazardous materials. The contents of such systems are considered to be animal-free or TSE-risk-free when the amount of remaining non-animal free or non-TSE-risk-free material is calculated to be NMT 25ppm. The next lot made after the bulk tank or system is animal-free is considered animal-free.
– Processing Aides or Components (e.g. ion-exchange and chromatography resins, carbon beds, filtration membranes) – Because of the porosity and absorptive nature of these materials there is no obvious or established way to assess or verify cleaning. If a cleaning process and test method were developed, it should be able to achieve NMT 25ppm residual. The preferred approach is to discard legacy process aides and components when the switch is made to animal-free or TSE risk-free processing or to dedicate and segregate such materials between legacy animal-containing and animal-free or TSE-risk-free processes.
Guidance 128 Filing Strategy for Specifications for Raw Materials used in API
Introduction:
This document recommends the strategy for the filing of specifications for raw materials used in the manufacturing of Active Pharmaceutical Ingredients (APIs). A common strategy if used by all affiliate sites, will establish consistency in the API raw materials registered specification and insure that only the minimum appropriate specifications are filed. The strategy is designed primarily for new products filings.
Practice:
Review of historical practices for filing API raw material specifications shows that the level of detail is varied across Site, from minimum filing appropriate for the intended use of the material, to large number of specifications of limited value and the related detailed analytical methods.
In order to provide consistency in filing API raw material specifications and regulatory flexibility, this guidance provides recommendations as to the level of specifications required for various categories of raw materials. The categories were defined based on common knowledge of manufacturing process and the level of specifications was established based on the nature of the material and its intended use of each category. Raw materials are categorized in six (6) groups.
General background
The major markets (USA, Europe, Canada, Australia, Japan, South Korea, Singapore) regulatory guidances do not provide specific instructions on what specifications to file for API raw materials but indicate that the specifications must be appropriate for their intended use. These major markets guidances are either directly using the ICH M4Q (guidance for the Common Technical Document (CTD)) or a slight modification of the M4Q guidance.
Extract fromM4Q, section 3.2.S.2.3: Control of Materials (Drug Substance):
“Materials used in the manufacturing of the drug substance (e.g. raw materials, starting materials, solvents, reagents, catalysts) should be listed identifying where each material is used in the process. Information on the quality and control of these materials should be provided.
Information demonstrating that materials (including biologically-sourced material, e.g. media components, monoclonal antibodies, enzymes) meet standards appropriate for their intended use (including the clearance or control of adventitious agents) should be provided, as appropriate.”
This strategy addresses only the registered raw material specifications defined as the test technologies and limits provided to “external agencies and are legally binding”. It is expected that PGM API sites will evaluate whether additional internal targets to control the quality of the incoming raw materials are required. Limiting the registered specifications to the minimum requirements allows for future flexibility to adapt to the commodity market for API raw materials, to advances in analytical technology, and to implement improvements without the need for changes in the regulatory filing. Quality of the raw materials will not be compromised, as the sites will use systems and internal targets to control and monitor performance of the suppliers.
General requirements for filing
– Analytical method: Specifications should be limited to a listing of the appropriate technology or method (i.e. HPLC, GC, NIR) with the associated limit. The details of the actual analytical methods or reference numbers should not be included. There may be some rare instances (such as an advanced intermediate or starting material that are close to the final API) where the analytical methods may be required but this should be the exception.
– Grade: Grade or tradename of raw materials should not be registered (i.e. Nitrogen instead of Nitrogen NF, Oxygen instead of USP Oxygen) and generic description is preferred (i.e. Carbon black instead of the carbon grade such as Darco). If a particular attribute of a grade has impact on the process or the API quality, only that attribute should be specified.
– Hazardous materials: The regulatory filing should clearly indicate that due to the hazardous nature of the material, it will never be sampled and tested by Site. The material will be accepted on supplier Certificate of Analysis data.
Categories Definition and filing strategy
For the purpose of this guidance, API raw materials were categorized into several groups for which a different level of registered specifications would be required. The categories are defined based on general “intended use”.
Category 1:
Raw materials in this category contribute to a significant portion of the final API molecule. This would include the regulatory starting material and registered intermediates. This category requires the highest level of specifications and should include at a minimum identification and a measure of purity. The specifications may also include impurities, optical properties.
Category 2:
This category includes any raw material that has one or more attributes that could impact the process or the quality of the API. The specifications should include the basic specification for the category of the raw material and in addition, the critical attribute. For example if a solvent (a category 3 raw material) had a very low moisture requirement for a specific step, the specification would include the category 3 specifications plus the moisture requirement.
Category 3:
This category includes materials that have a minor contribution to the final API molecule (such as addition of a Carbon atom to the structure), or provide a protective group which is subsequently removed. This category also includes solvents, acids and bases. In addition to the identification test, typically a measure of the purity of the material would be required.
Category 4:
This category includes basic raw material such as salts. The recommendation is to limit the registered specification to the identification test. Category 4 also includes processing aids; however, according to ICH Q7A 7.32, these materials can be received on COA. The identification test in the case of processing aids, if registered, should be transcribed from the supplier’s Certificate of Analysis
Guidance 129 Labeling of APIs and API Intermediates
Introduction
Containers for APIs and API Intermediates should bear labels that give at least the following information:
– The name of the material,
– Site material identification code,
– Amount of material,
– The batch or lot number,
– The expiry date (if applicable),
– Any special storage or handling conditions, and
– The manufacturing site and contact information.
As appropriate, the grade or pharmacopoeia status, International Nonproprietary Name (INN) or country specific label information should be included. Certain APIs or intermediates for US import or export must be also bear label text consistent with FDA drug listing requirements.
Practice
The recommendations and requirements presented in this document are based upon Quality Standards and guidance documents published by the World Health Organization (WHO), the International Conference for Harmonization (ICH), the US Pharmacopoeia (USP), the European Pharmacopoeia (EP), the US Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicines (EMEA).
- Recommendations and Requirements for Labels
- General Requirements for Labels
– Labels should be clear, unambiguous, and permanently affixed to containers
– Labels should follow an approved Site format, bear a label code number with revision code
– The information on the label should be indelible
- Minimum Requirements for Label Content
– Identification Name(s), including International Nonproprietary Name (INN) if Applicable
– Grade (e.g. Sterile, Injectable, Veterinary) if applicable
– Site article number
– Manufacturer or re-packer lot number or batch number
– Pharmacopoeia reference (e.g. USP, BP, EP, JP) if applicable
– If a controlled substance appropriate codes must be included
– Stability, Storage or Handling Information
– Expiry date, if one exists; if a retest interval exists, a retest date may be included on the label or the certificate of analysis
– Special storage or shipping conditions – based on formal stability studies and per requirements of EMEA/CVMP/422/99-Rev2 or CPMP/QWP/609/96/Rev 1
– Handling precautions and safety information – may be presented on a separate label
– Contact Information
– Name of manufacturer and site of manufacture
– Contact details for manufacturer
- United States Requirements and Recommendations for Labelling
- US Importation Requirements
– An API for import to the US must have labelling that lists adequate directions for its use unless it is meets the exemptions from labelling defined by CFR 201.122:
– The API container bears labelling such as “Caution: For manufacturing, processing, or repacking” or when an approved drug application doesn’t exist the container bears labelling such as “Caution: For manufacturing, processing, or repacking in the preparation of a new drug or new animal drug limited by Federal law to investigational use.”
– An API (and its manufacturer and recipient) must be included in an FDA approved new drug application (NDA) or a new animal drug application (NADA), an abbreviated new drug application (ANDA) or an abbreviated new animal drug application (ANADA) or an investigational new drug application (IND) or an investigational new animal drug application (INAD).
– APIs used only in human OTC drugs or in human prescription drugs that don’t require a new drug application are exempt.
- United States Drug Listing Requirements
– Before a foreign plant (affiliate or third party) can ship to the US for the first time an API or drug product for human or animal health use, the manufacturer must list the API or drug product with the FDA Drug Registration and Listing Office.
– Third Party Manufacturers (TPMs) must identify a site affiliated US agent to act as the contact with FDA on their behalf.
– FDA drug listing is required for all API’s manufactured in a foreign facility and used in human pharmaceutical products (Rx or OTC) marketed in the US .
– FDA drug listing is required for all materials regulated as controlled substances EXCEPT when the material is transferred between affiliate plants within the US / Puerto Rico.
– FDA drug listing is NOT required for intermediates, drugs used in clinical investigations or for non-clinical research purposes EXCEPT if they are considered to be controlled substances.
– FDA drug listing is NOT required for APIs used exclusively in animal health products EXCEPT if they are imported to the US, exported from the US or are controlled substances.
Guidance 130 Post Approval Equipment Changes to API Manufacturing Processes
Introduction
API equipment changes after the final intermediate only require a revision to registrations if the equipment has been explicitly described in a registration commitment or if pre-/post-change chemical and physical equivalence of the API cannot be demonstrated or if there is an effect on the drug product.
Practice
The expectations or requirements for API equipment changes defined in FDA or other Health Authority guidance DO NOT extend beyond the language of the registration commitment defined by the current registered API Regulatory Process Description (RPD) EXCEPT when appropriate chemical and physical equivalence of the API cannot be shown or when the change is shown to have an effect on the drug product. This position applies to API registration commitments described in NDAs, ANDAs, NADAs, ANADAs, Drug Master Files, Certificates of Suitability, Marketing Authorizations or equivalent regulatory documents.
Consistent with FDA BACPAC I Guidance, equipment changes prior to the final intermediate need not be reported even if the equipment has been specified in the approved registration. The elements of the site work process for API equipment changes after the final intermediate are:
- The sponsor of a proposed change prepares a protocol to demonstrate equivalency of the API before and after the change.
- The equivalency protocol is reviewed and approved by site Quality Operation, Process Technology and Manufacturing Services.
- A Product Change Proposal (PCP) is prepared and sent to Manufacturing Compliance describing the proposed change and requesting an assessment of the change against the language of the approved Regulatory Process Description (RPD) and any other registration commitments that describe API manufacturing.
– If current process equipment is explicitly described in a registration commitment, a revision to the registration may be required prior to the site implementing the change.
– If current process equipment is not explicitly described in a registration commitment and equivalence of the API and drug product can be demonstrated, no registration update is needed.
- The sponsor of the change decides whether or not to proceed based upon the regulatory assessment and results of the equivalency study.
- Once a particular type of equipment change has been established as equivalent for a given API process and the registration reviewed by Manufacturing Compliance and revised as needed, subsequent interchanges of such equipment for a specific API process may be handled at the site level and need not be reviewed by Manufacturing Services.
General Discussion
The filing requirements presented in guidance documents, such as FDA’s Guidance to Industry – Changes to an Approved NDA or ANDA, should be applied only to the specific information and language of the registration. The General Requirements section of the FDA guidance states
“An applicant must notify FDA about each change in each condition established in an approved application beyond the variations already provided for in the application (§ 314.70(a)(1)).”
This statement is interpreted to limit the applicant’s reporting accountability to the conditions established in the approved application.
During the development of API manufacturing processes, the critical process parameters are established in an integrated manner with the critical quality attributes for the API and drug product. The RPD captures this information for review and approval by health authorities. The language of an RPD is intended to capture the critical elements of API manufacturing, to provide justifiable manufacturing flexibility and to define the regulatory commitment to interpret GMP compliance. Extension of the expectations or requirements of FDA or other Health Authority guidance documents beyond the agency-reviewed-and-approved manufacturing commitments for APIs is counter to the concept of reducing the regulatory burden for the pharmaceutical industry