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Developing the Formulation for Clinical Trials
| 작성자 | 관리자 | 카테고리 | 전문가 인사이트 |
|---|---|---|---|
| 작성일 | 2016-04-26 | 조회수 | 1,246 |
| 원문 | |||
| 출처 | |||
Developing the Formulation
for Clinical Trials
- 글 Richard Buchta
- GPKOL위원
학력사항
- 2006 Deakin University / Financial Management / MBA
- 1987 Weizmann Institute of Science / M.S, Ph.D
- 1979 Monash University / B.S
경력사항
- 현재 Director, Formulytica Pty Ltd
- 2014-현재 CEO, RBR Pharma Consulting
- 2001-2014 R&D & Operations Senior Director, Stiefel Research Australia
- 1999-2001 New Product Project Manager, Wyeth Australia Pty Ltd
- 1998-1999 New Product Development R&D Project Manager, AstraZeneca Pharmaceuticals
- 1990-1998 Project Manager, Fort Dodge Australia Pty Ltd
- 1988-1990 Research Scientist, Pacific Biotechnology Ltd
세부 전문분야 및 컨설팅 내용
- 피부과학 및 백신 분야 신약개발
- 제형 및 분석적 개발(Formulation and analytical development)
- 글로벌 신약 발굴을 위한 연구 기획, 전략수립 및 프로젝트 관리
- R&D기획 : 프로젝트 제안서 초안 기획 및 진행중인 프로젝트 관리
- PM : 지역과 글로벌 백신 및 피부과 제품 R&D 프로젝트 인허가 관리
- 생산(GMP) : GMP 및 생산 시스템 개발, 포뮬레이션 확대 생산, 생산 과정 및 시스템 기획
- 기술마케팅 : 마케팅 계획과 기술데이타의 접근성 개발, 마케팅 및 비즈니스 기획 초안, R&D 프로그램의 마켓 연구
ABSTRACT
Developing the formulation or Chemical Manufacturing & Controls (CMC) information of awell-characterized and stable formulation is one of the most important aspects of preparation for a clinical trial.The formulation or more particular the drug substance formulated is what is to be evaluated for efficacy and safety.
Too often in the effort to initiate and produce clinical results the product formulated has not been through physical chemical evaluation and robust stability assessment, despite being approved by the regulatory authorities to initiate clinical trials. Thus the clinical trial may not go ahead, be delayed or may produce inconclusive results as a result of a poorly developed product.
The approachis outlined fordeveloping a well characterised and stable formulation,from rigorous product development generating robust manufacturing and physico-chemical stability data to support a pre-clinical Proof of Concept and Phase 1-2 programme. Thus, the focus is on the clinical trial outcome and result not questioned over the qualityand safety of the drug product.
This article highlightssome of the key factors that drive the processes behind and contribute to rigorous product development. Including i) clear product profile ii) understanding of chemistry of drug active and of existing formulations iii) chemistry of drug active in formulation, expected performance and experimental evaluationiv) design of experiments. This approach is not at the expense of time and budget in commencing a clinical trial, but ensures the right formulation of the drug active is being evaluated and the formulation does not to be redeveloped.
INTRODUCTION
Developing the formulation for clinical trials is basic to understanding how a drug will impact clinically both in efficacy and safety. Defining the formulation for the drug upfront can be a challenge.Rapid formulation prototyping and evaluation can be critical for company cash flow and survival with the drug product developed for medical and business need. The medical need is obvious, but the financial return will often drive business case to develop.
Marketing requirements should be addressed in development. This should be done early in development and again prior to Phase 2. The drug formulation is often developed to get initial positive data but then usually never redeveloped to be more appropriate for its intended use.
The key to developing a formulation therefore is to understand the chemistry of the drug substance, delivery system, packaging, fit for use and indication – all the basics, and in which quality is a key attribute.
Regulatory requirements (eg. United States Food &Drug Administration(FDA) Guidelines) which are well defined and form the basis of development and in particular the discussion between developer and the regulatory authorityduring the development.
A new formulation or delivery technology evolves based on drug substance chemistry. The vehicle can be dependent on consumer preference, indication or drug substance chemistry. While patents can throw up roadblocks the patent landscapecan often be travelled and lead to new patentable findings.
Most problems with formulation and consequently mistakes arise due to pressure of time and budget and to meet investors/management timelines to have data for next round of funding or license or Stock Exchange listing. Data review competes with this to drive next steps in formulation development.
Drug product development has a number of competing priorities, including:
- Drug Substance Chemistry
- Indication
- Target
- Formulation
- Drug Delivery
- Efficacy
- Safety
- Marketing
- Management Budget
- Investors
All of these and more need to be built into the Target Product Profile (TPP) and development plan.
The article will focus on topical (dermatology) product development for clinical trials.
WHERE TO START
Often a developer looks for a place to start, not so much what the drug or indication is but where to start in actually developing formulation, ingredients, incorporation and release of drug from the formulation and packaging.
First understand what the need is. From there start to build the Target Product Profile. Questions to ask include:
- what is it that you want to developand how the drug is be formulated and delivered
- what is the indication or therapy area
- what should the product look like
- how it will be delivered
- where is the drug required to end up
- desired Chemistry, Manufacturing Controls (CMC), safety and efficacy outcomes
- regulatory pathway
- manufacturing capability requirements and location
- distribution channels
- marketing outline for intended markets including competitors
- reimbursement
- budget
All the above and more impact on how the final form of the drug product will evolve.
FORMULATION
Developing the formulation for clinical trials follows drug discovery and initial safety and in vitro and animal in vivo efficacy.Prototyping of a formulation may also occur early on as a simple solution.
The formulation development may include exploitation of an existing drug delivery technology, possibly under an existing patent or may be the first product to require or exploit a new delivery technology
Drug Substance
Understanding the physico-chemical properties of the drug substance for formulation is key to understanding the requirements, and performance of the drug product. Apart from synthetic pathway and related substances, important in the analytical studies and impurity limits, stability under environmental conditions of temperature, light, oxygen and pH and compatibility with excipients is important with respect to potential degradation pathways of the drug.
The physico-chemical properties also will relate to the desired performance that the formulation will be developed around such as controlled release, bio-absorption rate and packaging compatibility. This will relate to the route of administration such as topical, oral or injectable.
Regulatory
In developing a drug product formulation it is important to be aware of the regulatory pathways of the market you are intending to launch the product. As most developers target the United States market, the FDA guidance’s and requirement are typically those that are followed. Other markets such as in Europe, Asia, Australia and Africa may have their own regulatory pathways but this is more related to pre-clinical and clinical studies, not as much as CMC. In fact, global guidance’s such as those of ICH for stability are now widely followed.
The United States FDA has typically a number of approaches for product development depending on whether the drug substance is a new chemical entity or a generic. Abbreviations such as NDA, ANDA, 505b(2) and orphan indication are used in the language of developers and business to describe these pathways. Depending on the pathway the route for the developer can be short or long, expensive or not with follow on implications for pre-clinical and clinical studies required.
For the developer, the Importance of safety is exposed as the developer reaches a near to final formulation. In the case of the products regulatory status:
- NCE: assume all known safety is from pre-clinical
- Generic: safety is well known from past pre-clinical and clinical so the focus is on new formulation and bioavailability
- For topicals, vehicle matters: eg. ointment vs cream vs solution
Suffice for regulatory, developing a product with the right information, complete information or just enough information for regulatory authorities to give approval for human clinical trials is a decision in the developers strategy. While most companies follow a “quick and cost effective strategy in line with minimal regulatory requirements this can come undone with technical challenges. Decisions should not be driven by cost and project timelines, but in practice a large part of project decision making should be driven by data and experience.
Drug Product Pre-Formulation to Prototype
Where to start after the drug substance physico-chemical properties are understood. And the target site of delivery and indication are known and the TPP requirements are understood.
In going from pre-formulation where the drug substance solubility is determined in potential excipients and if not soluble, the particle size and suspension properties evaluated. Analytical methods are developed concurrently as the formulation evolves both quantitative (drug substance and degradants) and qualitative (physical) as this early work if planned will allow not only solubility but simple stability to be evaluated in this simple matrices. Existing or developing in vitro activity of the drug substance in these simple matrices and prototype formulations allows screening of formulation performance, thus further enabling a development pathway to the final formulation
It is at this time as the formulation develops one starts to consider scale up and manufacturing site capabilities,preclinical safety: in vitro and in vivo animal efficacy if available, which contributes to a feedback loop to iterate formulation
Excipients
The choice of excipients is decidedbysolubility or suspension of the drug, stability, the vehicle indicated by the TPP based on indication, packaging and use, excipient chemistry and availability in usually pharma grade and listing on the FDA Inactive Ingredient database.A the formulation develops and initial screening for in vitro activity and safety occurs, this then acts as a feedback loop on choice or level of excipient required.
Analytical
Developing analytical methods for drug substance and drug product is an important part of product development to characterise the product and to monitor stability within defined specifications either pharmacopeia, ICH or in-house.
Key analytical method is typically drug substance quantity or potency and appearance of drug related substances or degradants, preservative and antioxidant, usually by developing an analytical HPLC method and validating on the final drug product.
Stress studies of the drug substance and repeating such studies in house can be of relevance in understanding drug substance stability especially in relation to heat, light, oxidative stress and pH extremes which helps to prototype formulation. This helps in developing the stability indicating method(s), and identification of potential degradants during storage.
Other analytical methodologies important for the drug product in characterising and assessing stability includepH, viscosity, particle size, appearance. If the product has typically more than 60% of water content the product as it is developed is assessed for microbiology preservation and microbial limits of growth as per pharmacopeia requirements. The need for addition of preservative is the justified rather than just added. Self-preservation is an important claim for drug products.
Method validation for all analytical methods is required for the final drug product when manufactured under GMP.
Other analytical methods include in vitro biological methodswhich can screen formulation prototypes eg, skin permeation, drug in vitro release testing, biology markers (may include in vivo). Rarely do these biological methods become part of the final product specifications.
Packaging
-
Packaging and packaging compatibility may impact formulation composition, viscosity and manufacturability.Topical packaging options of tube, pump pack or spray will require consideration of scale up and manufacturing site capabilities. Consideration for packaging interaction with the various types of packaging materials such as i) plastic - different laminates, linings, ii) aluminium tube – still do “scratched” to check drug: aluminium interaction iii) Pump - metal spring interaction by priming and iv) aerosol can - lining and gaskets
Quality by Design
Quality by Design (QbD) is a systematic approach that formalizes product design, automates manual testing, and streamlines troubleshooting. By its incorporation in product development it ensures quality by developing a thorough understanding of the compatibility of a finished drug product to all of the components, such as excipients and packaging, and processes involved in manufacturing the product. Troubleshooting issues related to the product and its manufacture then doesn't rely on finished product testing alone. It becomes useful in Out of Specification investigations as well as customer product complaints.
Where it should be incorporated in product development is during product development, not after a final product is achieved, albeit some further studies may be required to complete the studies.
Quality by Design and the design space of formulation and process involves Identification of all critical formulation attributes and process parameters, determining the extent to which any variation can impact the quality of the finished product. Such attributes may include:
- extremes of pH,
- range in composition by % of critical excipients such as thickeners and effect on viscosity and drug release
- pump speed fast-slow for oil/water mix
- viscosity extremes
- aged excipients vs. new
- same excipient different supplier or same supplier different batch or manufacturing site
The more information generated on the impact – or lack of impact – of a component or process on a product’s quality, safety or efficacy, the more flexibility QbD provides.
Manufacturing
Scale-up from laboratory to pilot to commercial scale covers amounts from <5 kg to 100 kg to >1,000 kg.Ideally, during this scale up the same vessel, geometry, mixer type, shape & size are similar as this reduces potential issues when scaling up and mixing issues arise. The appropriate vessel and volume for required batch size is important but this is often limited by the in-house manufacturing or the Contract ManufacturerOrganisation capabilities. Recall it is important to bear in mind manufacturing requirements and capabilities early in product development. Analytical capabilities are also important when assessing manufacturer as they may have to outsource certain testing, depending on the drug product and specification requirements.
Once the product is manufactured, in-process testing prior to fill and during fill as well as release testing is required.
From manufacture to fill to final packaging of inner and outer packaging must be considered early on so changes can be made if required. Filling line may have certain viscosity requirements or speed of line. When considering manufacturers audit there actually capabilities to fill your product as you know it. While developing a product for a specific manufacturing capability or site could be advised, this should not limit the other aspects of product performance. Above all in developing the product keep in mind that the manufacturing process should be simple. Developing a manufacturing process to accommodate a unique product can dramatically increase cost of goods.
As part of QBD, critical process parameters should also be considered for scale up from pilot to commercial scale. These include:
- Order, rate of ingredient addition
- Heating and cooling rates
- 2 or more phase process
- Design of Experiments and QbD risk minimization
- Critical Quality Attributes of process and ingredients
- In-process testing
- Filling
PRE-CLINICAL
Pre-clinical safety studies are typically carried out pre-Phase 1 (small scale, multiple species), pre-Phase 2 and pre-Phase 3 (large scale, single species, and longer duration). Formulation excipients are typically well understood and the safety is more focussed on the drug substance and its combination with excipients, although vehicle controlled assessments are usually carried out. There is a move to in vitro assessment eg. Mat Tek EpiDerm™(for topicals, in vitro model system for chemical, pharmaceutical and skin care product testing), driven by government and regulatory requirements, although animal in vivo assessment is still commonly used. Specific animal safety tests have been decided for indication and dosing and duration of proposed human clinical trial and treatment, eg acne.
Safety can be directed to assessing formulation evolutions, although this is more likely to be in vitro.
In animal studies, conservatism is the norm and number of animals, actual required safety studies as per guidance(s) or negotiated with regulatory authority and dosing regimen and duration of safety studies are considered as part of protocol and ethics approval.
Typical animal studies are vehicle (placebo) controlled, ie, there is a group which is treated with vehicle only, and maybe at maximal feasible dose based on pre-clinical. For most drug substances the first indication of developed formulation safety issues, usually not final formulations
Question of GLP (Good Laboratory Practice) (non-cGMP) and cGMP material for use in GLP studies is commonly asked. For regulatory submission it is GLP. However, guidance's do not really go into any detail as to what exactly is required as the quality for GLP depends on what is considered“well-characterized” for the product on a case by case basis. Generally, the GLP material can be a well-documented (batch record with QA sign off) laboratory batch that has been chemically characterized for API identity and purity (can be a manufacturer’s Certificate of Analysis, drug substance concentration (validated analytical method). The drug product used should be checked for stability over the time course of the study (either on stability during the study under the same conditions as storage at the study site) or analyze the dose material before and after the dose administration timing of the study to show Regulatory Authorities that the dose was accurate and stable.
HUMAN CLINICAL TRIAL
For the assessing a drug product in a human clinical trial whether it is a prototype or a final formulation, and only some indication of efficacy pre-Phase or Phase1/2 one should note that the formulation should be well understood in terms of stability, manufacturing, analytical
Scale: R&D to manufacturing/pilot to commercial scale
GMP for regulatory enabling studies, although laboratory batches can be used in some markets
However, in development one should develop to 1-100 kg scale depending on scope of enabling pre-clinical, Phase 1 clinical or direct to Phase 2 clinical studies
Typical manufacturing batch sizes will depend on clinical trial requirements of number of patients and formulation stability protocol assessment:
- Phase 1
Safety, single arm or additional arm of vehicle control, limited efficacy, minimum number of patients, typically <1-5 kg required
- Phase 2
Safety, multiple arm dose ranging vs vehicle control, may require 20-100 kg
- Phase 3
Safety, active arm vs vehicle control, may require 100-1000 kg
Stability of the batches regardless of size should be carried out from release of product to end of study,at typically 2-8, 25, 30 and 40oC based on ICH guidelines per market and zone. For larger batches and if opportunity avails itself, then longer term stability studies should be carried out or at least 6 months 40oC, with preference to 27months at 25oC.For Phase 3 clinical trials the developer should develop to minimum 1/10 commercial scale, in anticipation of commercial batches for registration purposes being required.
QUALITY ASSURANCE SYSTEMS IN PRODUCT DEVELOPMENT
Quality Assurance (QA) Systems in manufacturing are well known and established and follow in general globally accepted guidance’s, often referred to as cGMP (current Good Manufacturing Practice). These quality systems are extended to pre-clinical animal studies (GLP or Good Laboratory Practice and clinical (Good Clinical Practice).
Quality systems in product development in the Research and Development Phase canbe overlooked or not well done in interest of time and cost to the company. Ideally the company should have QA systems, maintenance and audit capabilitiesin place.Large pharma do it well, whereas small companies and start-ups tend to be in catch up mode as to when they realise they need QA capabilities.
The importance in rigorousdata recording especially in new product development is relevant for not only regulatory but also patent and future possible litigation but more importantly for potential business opportunities in out-license and acquisition. Poor data recording in the mistaken belief of getting quicker to clinic, is an issue and in the longer term does not serve the company.
SUMMARY
In developing a drug product formulation for clinical trials, the developer must know what they want to develop, and is based on the target product profile.Understanding the chemistry, biology, and target delivery of the drug substance and the delivery system chemistry and performance – limitations will guide the drug product development. Finally, knowing what you want to do beyond the initial drug product development in manufacturing, regulatory, pre-clinical and clinical can help the development of the drug product formulation so that it developed right eth first time.
Early robust product development in formulating a stable product will minimize poor pre-clinical and clinical outcomes, bearing in mind a focus on drug safety and efficacy, not at expense of time and budget. The right ingredients, ideally listed on FDA inactive ingredient databaseaidsthe formulation regulatory hurdles. If using a new or non-listed excipient be prepared for some level of additional and possible comprehensive safety testing. This can be aided by obtaining regulatory agency input early in the development.
Finally, with emphasis, spend time to understand the chemistry of the drug substance, solubility, crystallisation, stability, compatibility, target site delivery expectations and how it can be formulated for its intended application.
Authors Company
Formulytica
Contract Research & Development Organisation
- Formulytica is a new Australian company specialising in formulation development, analytical science, and project management. Developing products for topical-dermatology (prescription, OTC and cosmetic) and ag-vet applications.
Who we are:
Scientists with average 20 years experience in formulation and analytical development with over 30 pharma product registrations in US alone.
What we do:
- Product and analytical development of semi-solid formulations and solutions of new chemical actives, generics and natural ingredients
- Australian, US, EU and Asia markets
- Develop patentable technologies and processes as part of product development and understanding competitor product and patents.
- Resolve existing formulation and analytical problems
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