MWS 2 TRN 5105 BDP Pharma Industry Regulatory Perspective.ppt

1、Pharmaceutical Regulatory Perspective,Presented by - Jonathan Woodburn, Vice President, Compliance & Validation,Regulatory Perspective,Regulatory Requirements for Pharmaceutical Manufacturing There is almost no other industry that touches the health and well-being of so many people as the Pharmaceut

2、ical Industry. The rapid growth of the industry created a need for a regulatory agency, to protect the people who place their trust in it every day. That agency was FDA, Food and Drug Administration of USA, founded in 1910. The FDA is charged with enforcing all the provisions of Food, Drug and Cosme

3、tic Act and Regulations. The Current Good Manufacturing Practices are part of FDA regulations, and interpret what the FDA believes to be good manufacturing practices, providing minimum requirements for the production of drugs that are Safe, Pure and Effective.,Regulatory Perspective,Apart from FDA,

4、there are some other regional regulatory agencies which are also governing the manufacture of pharmaceuticals. We will see briefly about this in later slides. The consumers trust in the pharmaceuticals industry is basically provided by cGMP and FDA. So to manufacture a new drug substances or any dru

5、g substance, it is important to abide by regulatory requirements. Regulatory requirements basically refers to the US FDAs Code Of Federal Regulations. Code Of Federal Regulations (21CFR) was published by FDA, in SEP29 1978.,Regulatory Perspective,Title 21 Code of Federal Regulations Parts 210 & 211

6、PART 210 & 211: The regulations set forth in these parts contain the minimum current good manufacturing practice for methods to be used in, and the facilities or controls to be used for, the manufacture, processing, packing, or holding of a drug to assure that such drug meets the requirements of the

7、 act as to safety and has the identity and strength and meets the quality and purity characteristics that it is represented to possess. The failure to comply with any regulations set forth in these parts then such drugs will be deemed adulterated under Section 501 (a)(2)(B) of the Federal Food, Drug

8、 and Cosmetic Act (the Act). The guidance given by the Act, for the manufacture of the API will be discussed briefly in the forthcoming sections.,Regulatory Perspective,FDAs Guidelines and Expectations Know the cGMP Regulations Comply with the cGMP Regulations Know your Products and Processes Commun

9、icate Problems to the Quality Unit Take responsible actions and document justifications Have a system for conducting Failure Investigations Consumer Protection is the Number One Goal,Regulatory Perspective,International Regulatory Agencies and CGMP Guidelines,Regulatory Perspective,cGMP Guidelines:

10、FDA expects appropriate cGMPs to be applied to all steps of an API manufacturing process, beginning from the use of starting materials. This includes, the validation of processes determined to impact the quality and purity of the API. The quality of a product ultimately depends upon the quality of t

11、hose producing it. Most errors are human errors of omission or commission due to boredom, carelessness or inadequate instructions. The agency recognizes that the stringency of cGMPs in API production such as the extent of written instructions, in-processes controls, sampling, testing, monitoring and

12、 documentation should increase as the process proceeds from early stages to final synthesis and purification stages. APIs not manufactured in accordance with cGMPs are adulterated under Federal Food, Drug and Cosmetic Act.,Regulatory Perspective,The major cGMP Guidance for the manufacture of API are

13、 as follows: First, and most important, that nothing should be undertaken without following the written, or documented, procedures. Quality Control checks of the environment, equipment, materials, labelling and packing must be carried out at every stage of operation. Raw materials must be stored and

14、 handled correctly, so that exactly the right materials can be used at all times. All facilities and equipments, together with the environment in which they are situated are to be properly cleaned and disinfected. Both production and support staff, must dress and behave as required, should be proper

15、ly supervised and correctly trained. All work must be undertaken accurately and precisely. Contamination of materials, of either viable or non-viable nature, must be prevented at all times. Ensure that only the correct materials all added. Make sure that every item is appropriately labelled at every

16、 stage of production. Accurate records are to be kept for every activity.,Regulatory Perspective,Guidelines for API Manufacture Code of Federal Regulations has given the guidance for the manufacture of API under Part 211. It has been elaborately discussed in the Code of Federal Regulations. We will

17、just go through the contents of Subparts. For further information refer the Title 21 Code of Federal Regulations Parts 210 & 211. A. Introduction B. Organization and Personnel Responsibilities of the Quality Control Unit Personnel Qualifications Personnel Responsibilities Consultants,Regulatory Pers

18、pective,C. Building and Facilities Design and Construction Features Lighting Ventilation, Air Filtration, Air Heating, Cooling Steam, gases, and other Utilities Plumbing, Washing and Toilet Facilities Sewage and Reuse Sanitation Maintenance D. Process Equipment Equipment Design, Size and Location Eq

19、uipment Construction and Installation Equipment Cleaning and Maintenance Procedures Equipment Cleaning Methods Validation of Equipment Cleaning Methods Clean in Place Methods Automatic, Mechanical, Electronic and Computer Equipment,Regulatory Perspective,E. Control of Raw Materials General Controls

20、Receipt, Sampling, Testing and Approval of Raw Materials Use and Re-evaluation of Approved Raw Materials Rejected Raw Materials Control of Recovered Solvents, Mother liquors and Second Crops Process Water Quality F. Production and Process Controls Written Procedures and Deviations Charge-in of Compo

21、nents Calculation of yield Equipment identification Sampling and testing of in-process materials and drug products. Time limitations on production Control of microbiological contamination Reprocessing,Regulatory Perspective,G. Packaging and Labelling Materials examination and usage criteria Labellin

22、g issuance Packaging and labelling operations Tamper-resistant packaging requirements for over-the-counter drug products Drug product inspection Expiration Dating H. Holding and Distribution Ware housing procedures Distribution procedures,Regulatory Perspective,I. Laboratory Controls General require

23、ments Equipment cleaning and use log Testing and Release for distribution Stability Testing Special testing requirements Reserve samples Laboratory animals Penicillin Contamination,Regulatory Perspective,J. Records and Reports General Requirements Equipment Cleaning and Use Log Component, Drug Produ

24、ct Container, Closure and Labelling Records Master Production and Control Records Batch Production and Control Records Production Control Review Laboratory Record Review Laboratory Records Distribution Records Compliant Files,Regulatory Perspective,K. Returned and Salvaged Drug Products Returned dru

25、g products Drug Product salvaging,Regulatory Perspective,Regulatory Filings To manufacture any drug substance, a filing related to the manufacturing process, site, facilities etc., is to be submitted to the Regulatory Agency i.e., US FDA. New Drug Application (NDA) or Investigational New Drug Applic

26、ation (INDA): A petition submitted to US Food and Drug Administration for approval to sell a new drug in the US market.,Regulatory Perspective,Drug Master File: It is a US type II Drug Master File relating to the manufacture of SCG/NDS in Singapore. It contains details of the manufacturing site, fac

27、ilities, operating procedures, and personnel, the final drug substance, its intermediates, the materials used in the preparation, packaging materials and other details of the manufacturing process. It is the responsibility of the Drug Master File holder to ensure that appropriate information in rela

28、tion to changes, deletions or additions to the DMF are up to date. The DMF is to be updated annually and it is required to notify the FDA relating to any changes during the 12 months period. If there is a significant changes to the information held in the DMF, then it is addressed by other means lik

29、e New Drug Application (NDA) or Investigational New Drug Application (INDA).,Regulatory Perspective,On Pharmaceutical sites every year, there must be a review of information included in the current version of Drug Master File (DMF) and an assessment whether any changes have been made since the last

30、update. This review will cover all details included in the DMF, like manufacturing site buildings and facilities operating procedures key personnel manufacturing process /equipment packaging methods/materials storage stability,Australian Regulations,Therapeutic Goods Act 1989 Is a commonwealth act O

31、bjectives: to provide a national framework for regulation of therapeutic goods so as to ensure their quality safety efficacy timely availability,Therapeutic Goods Act 1989,Sets out the legal requirements for import export manufacture supply of medicines Details the requirements for listing or regist

32、ering all therapeutic goods in Australian Register of Therapeutic Goods (ARTG) Details other aspects: advertising labelling product appearance,Role of TGA,Therapeutic Goods Administration (TGA) carries out activities to ensure that all therapeutic goods available are of acceptable standard Australia

33、n community has access, within a reasonable time, to therapeutic advances.,Role of TGA,Pre-market evaluation and approval of registered product Licensing of manufacturers in accordance with international standards under GMP Post-market monitoring and response to public inquiries Development, mainten

34、ance and monitoring of systems for listing of medicines Assessment of medicines for export,TGA and Risk Assessment,TGA uses a “risk assessment” approach to regulate medicines Factors to determine products risks: it contains substance scheduled in Standard for the Uniform Scheduling of Drugs and Pois

35、ons (SUSDP) its use can result in significant side effects it is used to treat life-threatening or very serious illnesses there may be adverse effects from prolonged use of inappropriate self-medication,Listed Medicines,Of lower risk than registered medicines Majority are used for self-treatment Con

36、tains only well known established ingredients Do not contain substances scheduled in SUSDP Assessed by TGA for quality and safety (not efficacy) Examples are herbal, vitamin and mineral products,Registered Medicines,Of higher level of risk Sponsors are required to provide comprehensive quality, safe

37、ty and efficacy data Must display AUST R number on label Two types: Non-Prescription (Low Risk) Registered (Examples are OTCs) Prescription (High Risk) Registered (Examples are prescription medicines and injectables),Pharmaceutical Regulatory PerspectiveLocal Regulations,Singapore Regulations On Med

38、icinal Products,Medicines Act Cap 176 of Statutes of Singapore Promulgated in 1977 Provide a comprehensive control of all aspects of dealings in medicinal and related products Provide for licensing of all medicinal products, manufacturers, etc.,Medicines Act,Part I - Preliminary Part II - License an

39、d Certificates Relating to Medicinal Products Part III - Further Provisions Relating to Dealing with Medicinal Products Part IV - Pharmacies Part V - Containers, Packages and Identification of Medicinal Products Part VI - Promotion of Sales of Medicinal Products and Medical Advertisements Part VII -

40、 Miscellaneous and Supplementary Provisions,Other Relevant Regulations,Poisons Act Cap 234 of Statutes of Singapore With Poisons (Hazardous Substances) Rules provide controls over the import, transport, storage and use of poisons or hazardous substances Misuse of Drugs Act Infectious Diseases Act Re

41、gulates import of disease-causing organisms Provides guidelines on the import, transport, handling and disposal of human pathogens Regulations on environmental control,MOH Organisation Chart,Minister for Health,Parliamentary Secretary,Permanent Secretary,Director of Medical Services,Deputy Secretary

42、,Planning & Development,Corporate Services,Information Communication,Elderly & Continuing Care,Health Sciences Authority,Epidemiology & Disease Control,Health Service Development,Health Regulation,Health Promotion,Professional Stds & Devt,Acronyms,CCG - Co-ordinating Centre for GCP CPP - Certificate

43、 of Pharmaceutical Product CRO - Contract Research Organisation CT - Clinical Trial CTC - Clinical Trial Certificate CTERU - Clinical Trials & Epidemiology Research Unit EC - Ethics Committee GCP - Good Clinical Practice HSA - Health Sciences Authority MAC - Medicines Advisory Committee MCRC - Medic

44、al Clinical Research Committee NCEs - New chemical entities,Major Government Agencies,The Health Sciences Authority (HSA) A new statutory board formed on 1 April 2001 Established by the integration of 5 specialised departments under the Ministry of Health Centre for Drug Evaluation Institute of Scie

45、nce and Forensic Medicine National Pharmaceutical Administration Product Regulation Department Singapore Blood Transfusion Service,The Health Sciences Authority (HSA),8 Centres: Centre for Pharmaceutical Administration (CPA) Centre for Drug Evaluation (CDE) Centre for Radiation Protection (CRP) Cent

46、re for Medical Device Regulation (CMDR) Centre for Transfusion Medicine (CTM) Centre for Forensic Medicine (CFM) Centre for Forensic Science (CFS) Centre for Analytical Science (CAS),Centre for Pharmaceutical Administration (CPA),Pre-market product evaluation and licensing Licensing of manufacturers

47、, importers, and wholesalers Evaluation and certification of clinical trials Assessment and certification of GMP Licensing of retail pharmacies Post-marketing activities Investigation and prosecution of illegal sale Licensing of retailers of tobacco products,Centre for Pharmaceutical Administration

48、(CPA),All clinical trials on medicinal products require a Clinical Trial Certificate (CTC) from CPA, HSA. The Medical Clinical Research Committee (MCRC) advises on the licensing of clinical drug trials.,Organisation Chart of CPA,Primary activities relating to control of Western medicines,Processing

49、applications for new product licences, amendment and renewal of existing licences. Approving the import of unregistered medicinal products on a named patient basis. Issuing permits for the import of medicinal products to be re-exported. Controlling the import of drugs, medicines and other related su

50、bstances through TradeNet system. Providing secretariat support for the Medicines Advisory Committee (MAC) and the Medical Clinical Research Committee (MCRC),GMP & Licensing Unit,Formed in April 1997 Scope: Licensing of pharmacies and dealers Regulation of psychotropic and narcotic drugs Granting of

51、 Certificate of pharma product under WHO Certification scheme,Life Sciences Cycle,Integrated Chain of Activities,Research,Emphasis on teaching of life sciences Increase in production of PhDs from NUS Increase in production of pharmacists MSc (Pharm), PhDs Production Quality control Clinical research

52、 assistants GMP inspectors Increase in production of pharmacists Grants CTERU (Clinical Trials & Epidemiology Research Unit),The Product,Production of IND (Investigative New Drug) No control presently To be manufactured according to GMP standards,Animal Studies,Are required Collaborate with various

53、science department of NUS,Clinical Development,Clinical Trials-In place Medicines (Clinical Trials) Regulation 1978 and its amendment (1998) Singapore Guideline for GCP 1998 (similar to ICH guidelines) CROs (Contract Research Organisations) Covance ICON ProPharma Quintiles,Support for Clinical Trial

54、s,Clinical Trials & Epidemiology Research Unit (CTERU) in the Ministry APEC Co-ordinating Centre for GCP (CCG) Quintiles - US GCP Training Programme SGH-GCP Training Programme Lilly-NUS Centre for Clinical Pharmacology Singapore-based CROs,APEC Co-ordinating Centre for GCP,Organise courses for resea

55、rch personnel Collates clinical trials and GCP information from APEC countries Set up of APEG CCG in Singapore Established pharmaceutical industry Efficient infrastructure presence of leading contract research organisations,Singapore GCP Programme,National effort co-ordinated by the Faculty of Medic

56、ine, NUS with: Singapore General Hospital Tan Tock Seng Hospital Ministry of Health Quintiles East Asia Pte Ltd To spearhead training of personnel involved in CT design & implementation.,Clinical Trials Cert Applications,Submitted through Ethics Committee (EC) - Institutional Level Medical Clinical

57、Research Committee (MCRC) - Ministry Level,Ethics Committees,ECs in hospital are formalised according to guidelines Vets applications and forwards recommendations to MCRC for consideration to issue CTC.,EC-Terms of Reference,To review investigators request to conduct CT To evaluate safety of on-goin

58、g trials. To ensure on-going trials are carried out in accordance with Singapore GCP guideline Medicines (Clinical Trials) Regulations To report change of protocol or termination of trials to MCRC To ensure that investigator has been issued a CTC before commencing,MCRC,Secretariat: CPA Composition o

59、f Committee Chairman:clinician involved in clinical research Secretary: qualified and experienced pharmacist/doctor Members:5 clinicians Guest members: as and when necessary eg application for CT of INDs,MCRC-Functions,Receives recommendations of ECs Reviews applications for INDs Make recommendation to Director of Medical Services for issues of CTC Receives and evaluates intermittent and final reports Evaluates reports Audits when indicated,Application Process for CTC,Manu