المادة 31من تعليمات صناعة الأدوية والمستحضرات الحياتية والمبيدات البيطرية وتسجيلها وترخيصها وتداولها رقم 4 لسنة 2021

تلغي هذه التعليمات أية تعليمات سابقة . ملحق رقم (ا) متطلبات GMP GMP Check List Client is kindly requested to have the relevant documents available in the audit meeting room or assure easy access at the respective documents storage place: 1. Site Master File (Check if the master file is the same as the actual) 2. List of products produced at the site 3.Organization charts (functions, reporting lines) 4.Job descriptions 5.Is there “Quality manual” to address the “quality systems” 6. List of the key personnel and their qualifications especially the Technical Director, QC, Quality Assurance and microbiologist to see if they are knowledgeable or not 7. Entrance (if they record the names of the visitors) 8. Personal a.Does the company have an organization chart b. Does the company have a written job description c. Are the people in responsible position have adequate authority to carry out their responsibilities d. Does the company have adequate number of personal with the necessary qualification and practical experience e. Are the responsible persons meet the qualification requirements 9. Documentation a. Do specifications describe is detail the requirement with which the products or materials used or obtained during manufacture have to conform b.Does manufacturing formula processing and packaging instructions state all the starting materials use and lay down all processing and packaging operations c. Do procedures give directions for performing certain operations, e.g. Cleaning, clothing, environmental control, sampling, testing, equipment operation d. Do records provide a history of each batch of product including its distribution and also of all other relevant circumstances pertinent to the quality of the final product e. Do documents designed, prepared, reviewed and distributed with care f.Do documents comply with the related parts of the manufacturing and marketing authorization dossiers g.Do documents approved, signed and dated by appropriate and authorized persons h.Do documents have clear contents, title, nature, and purpose i.Do documents regularly reviewed and kept-up to date j. Are the documents printed and not handwritten and the entries made in clear, legible and indelible handwritten k. Does any alteration made to the entry on a document signed and dated, permit the reading of the original information where appropriate , the reason for alteration l. Are the records made or completed at the time each action is taken m.Are all significant activities concerning the manufacture of medicinal products are traceable n. Are the records retained for at least one year after the expiry date of the finished products o. Are only authorized persons be able to enter or modify date in the computer and there is a record of changes and deletions p. Does the access restricted by passwords or other means and the results of entry of critical data independently checked q. Does batch records electronically stored protected by back-up transfer or magnetic tube, microfilm, paper or other means and the date are readily available throughout the period of retention 10. Documents Required a. Are there appropriately authorized and dated specifications for starting and packaging materials and finished products, where appropriate for intermediate or bulk products b.Is there an authorized manufacturing formula and processing instructions for each product and batch size to be manufactured which include all basic information required by GMP’s c.Are there authorized packaging instructions for each product, pack size and type, which include all basic information, required by G.M.P d.Before any processing begins, are there recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned process and that equipment is clean and suitable for use. e.Is there a batch packaging record kept for each batch or part batch processed f.Does the packaging record carry the batch number and the quantity of bulk product to be packed as well as the batch number and the planned quantity of finished product that will be obtained g.Before any packaging operations begin, are there recorded checks that equipment and workstation are clear of previous products documents or materials not required for the planned packaging operations and that equipment is clean and suitable for use. h. Does the packaging record include all information that interned at the time each action is taken and after completion, the record is dated and signed in agreement by person(s) responsible for the packaging operaions. 11. Warehouses a. System for Good Storage Practice (protocol) b.Weighing room c. Sampling room d.Check if sampling tools are available e.Check the cleanliness of sampling tools f. S.O.P for cleaning of sampling tools and weighing room g.Check the weighing checking and double checking h.Receipt and storage of raw materials (system and records) i. Computer control system (locations and withdrawal) j. Temperature mapping in warehouses k.Check how they select the locations of the thermometers l. Temperature and humidity records for the last two years in the stores of API’s and finished products especially in summer m. Quarantine Area (list of products) n. Check the storage conditions mentioned on the outer packs and compare the temperatures o. Pests traps p. Is if there is an adequate pest control program q.Check the availability of refrigerator for storage of certain products r. Ask for a list of such products stored in the refrigerator? s. Storage of labels (separate area) t. Are the packaging materials separated in special area not accessible to every body u. Crowdedness of the store v. Ask who stick the labels on containers (QC or store keeper) w. Are storage areas of sufficient capacity to allow orderly storage of the various categories of materials and products x. Are storage areas designed or adapted to ensure good storage conditions (clean, dry, temperature and humidity) y. Are receiving and dispatch bays protect materials and products from the weather z. Are reception areas designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage aa. Does quarantine area clearly marked and their access restricted to authorized personnel bb. Is there a separate sampling area for starting materials cc. Are there segregated areas for the storage of rejected recalled or returned materials or products dd. Are highly active materials stored in safe and secure areas? ee.Are printed packaging materials stored in safe and secure areas? 12.Rejects Area a. List of Products available in this area b.Check if there are rejects label on each materials c. Are rejected materials adequately controlled? d. Is the area physically separated? e. Are rejected materials and products clearly marked as such and stand separately in restricted areas, waiting for action, which is approved and recorded by authorized personnel. f. Does the recovery of all or part of earlier batches, which conform to the required quality by incorporation into a batch of the same product at a defined stage of manufacture authorized beforehand according to a defined procedure and recorded g. Are product returned from the market and which have left the control of the manufacture destroyed unless without double their quality is satisfactory , they may be considered for re-sale, re-labeling or recovery in a subsequent batch only after they have been critically assessed by the quality control department in accordance with a written procedure 13. Sampling a.Does the sample taking done in accordance with approved written procedure and follow GMP requirements b. Are reference samples representations of the batch of materials or products from which they are taken c.Does sample containers bear a label indicating the contents with batch number, date of sampling and the containers from which samples have been drawn d. Do reference samples from each batch of finished products retained till one year the expiry date e.Do samples of starting materials (other than solvents, gases and water) retained for at least two years after the release of the product if their stability allows. 14. Coding System a. Coding system for raw materials b.Coding system for packaging materials c. Coding system for finished products d. Coding system for categories of documents e. Coding system for equipment 15. Labels and Labeling a. "Calibrated" label b. Notification of rejection packaging materials c.Notification of rejection raw materials d. Release label of packaging materials e. Release label of raw materials f. Check if the number of container is printed on the label and containers g. Quarantine label h. Reagents label i. Release for label j.Sampled k. Sampling of packaging material label l.Sampling of raw materials label m.Check the numbering the containers and if the containers are tested n. Check if the labels contained the needed information o. Check if the labels can be easily removed. 16. Quality Control a. Are quality control laboratories separated from production areas b. Do control laboratories have sufficient space to avoid mix-up and cross contamination during analysis c. Do control laboratories have adequate suitable storage space for samples and records d. Are there separate rooms to protect sensitive instruments from vibration, electrical interference, humidity etc,. e.Are there special requirements for handling particular substances, such as biological or radioactive samples f. Proof that ID test is carried out for every container of API g. Check the chromatograms and compare the results h.Take an API container, record the number , batch number and check if it has an identification test, in addition to composite sample testing i. Check the availability of reference standards j. Storage of working and reference standards k.Check the availability of working standards and compare potencies. l.Check the storage of reference and working standards m. Retesting protocol if available and if retesting is conducted n.List of analytical OOS o. Failure investigation S.O.P p.Change control System q. Check the standardization of reagents used for titrations r. Check the availability of specifications during analysis s. Compare the analysis results with specifications t. Log books for analysts and equipment u. Water used in QC v. Lab reports generation w. Review the COA if it contains all important physical and chemical tests x. Check if they have reviewer for analysis y. Residual solvents analysis z. Lab (QC) numbering system for traceability of materials aa. Microbiology section i. If sterility testing is carried out ii. If pyrogen testing is carried out iii. Bacterial count testing iv. Identification of bacteria v. Availability of two autoclaves vi.Availability of two laminar flows vii.Traceability of destruction the microbiological medias and microorganism viii.HVAC system for microbiology section bb. Trend analysis protocol cc.Source of reference standards dd.Are raw data kept well? Are they kept with the batch record? ee.Compare the results mentioned on the certificate of analysis with that of the log book for three dosage forms ff. Check the solvents used during the analysis if they have details needed? gg.Check the reagents used during analysis if they are expired or not? hh. On what basis they determine the shelf life of the solvent? ii. Retained samples room jj. Check if samples of batches are available, take random batch number? kk. System for working standards generation ll. PQ (performance qualifications) protocols for HPLC mm. Special area for toxic\hazardous materials nn. Check the suitability of lab equipment for analysis of products oo.Check the test results of penicillin cross contamination between facilities 17. Quality Assurance a.List of standard operating procedures (S.O.P’s) (index with approvals) b. List of rejected batches c.Calibration master plan d. Documents control procedures e. Documentation Center f. Check the expiry and updating of documents g. Batch release system h. Retained goods (system , disposal and records) i. Yield of products (percentages, system and records). Case study of low yield? j.Check the scientific validity of protocols and methods of analysis k. Visit the documentation center l. Is there an internal quality audit program (self inspection program) m.Check the (report) results of such self inspection n.If there is such self inspection program ask for records (report) o. GMP declaration form the suppliers p.DMF from the suppliers q.Certificate of analysis from the suppliers r. Non compliance list of products s. Corrective and preventive actions t.Level of involvements of QA in OOS u.List of change control system "products" v. Ask for log book for reprocessing w.Training assessment record for analyst x. Level of analysis of raw materials and finished products y.Trending of deviations z.If animal house available check the cleanliness and control aa.Adequate documented investigation into reasons for rejection bb. List of relevant process changes cc. Change control system dd. Waste disposal system ee. Check the shelf life of the documents? ff. Check if there are some in updated documents? gg. Check the availability of documentation system for documents? hh.Significant standard operating procedures, covering the subjects mentioned above ii.Toll manufacturing agreements jj. Technical agreements kk.Specifications of raw materials ll. IPC specification for each product mm. Release specifications nn.Shelf specifications oo. Environmental control pp. Check the approvals of the documents? qq.Check the list of documents distribution to the departments? rr.Check if the formats of the documents if it fulfills the GMP needs? ss. Determine the time needed to bring a document? 18.RD Department a. Stability protocols i. Accelerated – two pilots and one smaller ii.Long Term – three batches iii.Ongoing – batch every other year iv. Stability protocol for sterile products. b. Check the temperatures in the stability cabinets? c. Check if the stability parameters cover the important tests? d. Check the bio burden of solutions during stability? e.Check the availability of preservative efficacy testing? f. Impurities profile? Known and unknown g. Dissolution profiles for tablets h. Dissolution profile for suspensions i. Establishment of a system for setting specifications of the sterile products j. Procedure for setting specifications of API k. Check the chromatograms and compare the stability schedules l. Formulation development m.Expert report for certain products. 19. Engineering a.Drawings of air pressure b. Layout of differential pressure inside manufacturing facility c.Layout of relevant facilities including personnel and materials flow d. Air handling systems and it validation e. Zoning (layout) f.Equipment qualifications g. Equipment log books i. Use log book ii.Maintenance log book h. Filters i. Records ii. Maintenance iii. S.O.P for changing filters iv. Specification sheets for filters i. Drains and sewage system j. Air locks 20. Ancillary Areas a. Are rest and refreshment rooms separate from other areas b. Are changing, washing rooms and toilets easily accessible and toilets easily accessible and appropriate for the number of users c. Are maintenance workshops far and separated from production areas d.Are parts and tools stored in production area in rooms or lockers reserved for that use 21. Equipments a. Does manufacturing equipment design located and maintained to suit its intended purpose b. Are maintenance operations not present any hazard to the quality of the products c. Are washing and cleaning equipment suitable and not source of contamination d. Does equipment installed in such away as to prevent any risk of error or contamination e. Do the production equipment parts that came into contact with the products not reactive or absorptive to such an extent that it will affect the quality of the product f. Are balances and measuring equipment of an appropriate range and precision available for production and control operation g.Does measuring , weighing , recording and control equipment calibrated and checked at defined intervals by appropriate methods (externally and internally) h. Does an adequate record of such tests maintained (related to point g) i. Does fixed pipe work clearly labeled to indicate the contents and where applicable the directions of flow j.Does water treatment pipes and where appropriate other water pipes sanitized according to written procedures, that detail the action limits for microbiological contamination and measures to be taken k. Doe defective equipment removed from production and quality control areas or at least be clearly labeled as defective 22. Facilities (premises) a.Are premises cleaned and where applicable disinfected according to detailed procedures b. Are lighting, temperature, humidity and ventilation appropriate and not adversely affect medicinal products or accurate functioning of equipment c. Are premises designed and equipped so as to afford maximum protection against the entry of insects or other animals 23. Production a.Are there self-contained facilities available for the production of particular medicinal products b. Are specific precautions taken and the necessary validation made before the principle of campaign working in the same facilities accepted c. Does production take place in areas connected in a logical order way d. Does the working and in process storage space permit the orderly and logical positioning of equipment and materials e.Does production interior surfaces (walls, floors and ceilings) smooth free from cracks and open joints and not shed particulate matters f. Are pipe work, light fittings, ventilation points and other services easy to clean and accessible from outside the manufacturing areas for maintenance purposes g. Are drains of adequate size and have trapped gullies h. Are production areas effectively ventilated with air control facilities (including temperature and where necessary humidity and filtration) i. Is there a separate weighing room j. Are premises for the packaging of medicinal products specifically designed and laid out so as to avoid mix-up or cross contamination k. Batch numbering system and if the batch number is repeated within the whole shelf life of product l. Availability of special area for inflammables m.The way they calculate the weights and volumes of solvents used in the manufacturing of liquid dosage forms. n. Check the availability of master formulas o. Production documents generation p.Lag time between granulation and compression? How calculated? q. Do they use metal detector or not for powder filling? r. Are times and dates fixed in the batch record especially for the critical stages? s. Levels of details in manufacturing and packaging batch record t. Check the availability of batch records u. Check the availability of S.O.P’s for cleaning of equipment and production areas v. Types of cleaning (Wet\dry) w.Check the sterilization procedures. x. Ask the production technicians and cleaners if they are trained on such S.O.P’s y.Check the floors if they have grooves z. Check the paints of the production area aa. Check if the machines are painted bb.Check and review one batch record of every dosage form cc. Check if they write the actual weights on the batch records dd. Reconciliation of labels ee. Plan for Petri dishes in the sterile area 24. Validation a.Do validation studies conducted in accordance with defined procedures and results and conclusion recorded b.Does validation study conducted for any new formula to demonstrate its suitability for routine processing c.Are validation study conducted in case of significant amendments to the manufacturing process, including any change in equipment or materials, which may affect products quality and or the reproducibility of the process d. Do processes and procedures undergo periodic critical re-validation to ensure that they remain capable of achieving the intended results e. Retrospective validation protocol f. Retrospective validation records g. Sampling thieves "unit dose" h. Prospective validation protocol, review such protocol. i. Prospective validation records j. Validation protocol for analytical methods k. Validation of autoclaves l. Validation master plan m. Cleaning validation n. Validation of computer system o. List of documents categories p.Check if the balances are centered or not q. Media fill for sterile products 25. Complaints a. Protocol b. Types of complaints c. Company answers to such complaints 26. Recalls a. Protocol b. List of recalls c. Reasons for recalls 27. Materials a. List of approved suppliers b. Criteria for selection suppliers c. Suppliers audit reports d. Are stores, storage areas restricted to authorized personnel e. Are materials adequately segregated to avoid mix ups f. Is there adequate system for the control of labels g. Are waste materials clearly identified in proper containers h. Levels of cleanliness in production areas and stores 28.Calibration a. Balances b. HPLC’s c. Spectrophotometers d. Thermometers e. Any other equipment need calibration f. Types of glass ware used especially the pipits 29. Water Treatment a. Flow of water map b. Test points c.Types of pipes (stainless steel or plastic) d. Charts for test points e. Schedule for frequency of testing f. S.O.P’s g. Methods of analysis h. Loops and temperature i. Specifications of waters used j. Alert and action levels k.Water for injection used and tests conducted l. Circulation of water for injection at high temperature m. Check the details of sanitation procedures if it is adequate or not (record to demonstrate that desired sanitizing concentration of chlorine had been reached, records of the sanitation time, recording of the flushing sequence, and records of the final level of chlorine after completion of flushing. 30. Restaurant a. Cleanliness of the kitchen 31.Medical checks (Personal Hygiene) a.Does detailed hygiene programs relating to health hygiene practices and clothing of personnel established and adapted b. Does all personnel receive medical examination c.Does every person entering the manufacturing areas wear protective garments d. Are the signs forbidden eating , drinking, chewing or smoking or the storage of their materials in the areas where the products might be adversely affected e. Ask for medical checks for people working in sterile area f. Ask for medical checks for people working in production g. Ask for medical checks for people working in restaurant 32.Safety measures a.Suitable clothes b. Goggles c. Masks (dust and gas) d. Fire fighting systems e. First Aids 33. Computer a. Do they use backup for computer data b.Validation of computer programs used to release product 34.Training a. Systems b.Records c. New Employees d. Good lab practice training e. cGMP Lectures f. Job description g.Training program i. Exit Interview ii. Training records iii. Is there a program for periodic re-training iv. Does the company provide training for all the personal whose duties take them into production areas or into control laboratories v. Does the personal receive training appropriate to the duties assigned to them vi. Does the company periodically assessed the continuing training program and its practical effectiveness vii.Does the company have an approved training program viii.Does the personal working in areas where contamination is a hazard given specific training ix. Does the concept of quality assurance fully discussed during the training sessions 35. References (Text books ) a. Pharmacopeias b. Analysis text book c. Pharmaceutical technology d. Microbiology e. Validation ملحق رقم (2) متطلبات ملف تسجيل الدواء 1. سبعة عينات أصلية من الدواء او المستحضر الحياتي او المبيد البيطري مستوفية الشروط للعبوات الداخلية والخارجية إن وجدت 2. سبعة نماذج من الملصقات الخاصة بالمنتج ولكل عبوة يراد تسجيلها 3. سبعة نشرات داخلية للمنتج المطلوب تسجيله 4. الملف الاداري: (Administrative Part)والذي يتم تعبئته حسب النموذج المعد من قبل المديرية معبأ تعبئة كاملة طباعة ولا يجوز حذف او ترك تعبئة اي من متطلباته والذي يتضمن: 1. شهادة تسجيل المستحضر في بلد المنشأ Certificate of Pharmaceutical productتفيد بأن المستحضر مصرح بتداوله وبيعه في ذلك البلد بنفس التركيب والمواصفات والاسم التجاري والعبوات تكون صادرة عن الجهة المختصة ومصدقة اصوليا. 2. شهادة\فاتورة سعر تفيد بسعر المستحضر في بلد المنشأ للجملة وسعر التداول للجمهور وسعر التصدير للمملكة. 3. شهادة تحليل للمستحضرات المستورده ونتائج تحليل مختبر الرقابة الدوائية في المديرية للمستحضرات المحلية والمستورده. 4. ان يكون الدواء المطلوب تسجيله قد مضى على تداوله مدة سنة على الاقل في بلد المنشأ أو احدى الدول المعتمده لدى المديرية. 5.طلب تسجيل Application Form 6. كتابة وصفة صرف المستحضر Product Prescribing Information 7. مقدمه عامة عن المستحضر الدوائي ويتضمن الصنف الدوائي وطريقة العمل A general introduction of the pharmaceutical product, including its pharmacologic class andmode of action shall be included. 8. ان يكون الدواء الاصيل (original) مسجلا على الاقل في دولتين اوربيتين او امريكا 9. نسخة من اللصاقات والنشرة الداخلية. Labels and packaging insert 10. يقدم ملف الدواء على شكل ورقياو الكترونيor electronicPaper submission(CTD) 5- الملف الفني اوالعلمي: (Technical Part) والذي يتم تعبئته على شكل ملف متكامل يحتوي جميع الدراسات المتعلقة بالمستحضر الدوائي او على نمودج CTD (Common Technical Dossier) (ملحق رقم 3) والذي يشتمل على: 1. مواصفات المواد الاولية )الفعالة وغير الفعالة) وطرق تحليلها Specifications of the active materials, excipients and its analysis methods 2. مواصفات المستحضرالنهائي(Finished Product specifications) المطلوب تسجيله وتشمل: -التركيب التفصيلي للعلاج او المستحضر الحياتي ويشمل المواد الفعالة والحاملة Composition of the pharmaceutical dosage form containing the active pharmaceutical ingredients and excipients -الكميات المستعملة فعلا في (تشغيلة) التصنيع القياسية Standard Batch Manufacturing Quantities -نبذة مختصرة لطريقة الانتاج المتبعة والفحوصات البينية التي يتم اجراؤها خلال الانتاج. Batch manufacturing Process and In Process Control Tests -طرق التحليل للمستحضر النهائي والتثبت Analytical methods and its validation -طريقة تحليل المواد الحافظة والمواد مانعة التأكسد ان وجدت في المستحضر Analytical methods of preservatives andAntioxidant included in the product -طرق تحليل الشوائب ومواد التحطم Analytical method for Impurities (known andunknown) anddegradation products -المواصفات القياسية للمواد المركبة للمستحضر من جهة مرجعية دستورية و شهادة تحليلها من المصنع (Manufacturer) او المورد (Supplier). -المواصفات الفنية للعبوات (Packaging Materials Specifications) المستخدمة ومدى ملائمتها للحفاظ على المستحضر طوال فترة الصلاحية. 6 - دراسات الثبات حسب متطلبات ICH وتشمل: أ_ دراسة ثبات تسارعية(Accelerated Stability Testing) للمستحضر على ثلاثة تشغيلات موسطة الحجم او انتاجية على درجة حرارة 40°C ورطوبة نسبية 75% لمدة ستة اشهر. كما تدرس السوائل والحقن على درجة حرارة الثلاجة ما بين 2-8 °C لمدة ستة اشهر. Accelerated Stability Study on three pilot or production batchesat 40°C with RH 75% for a period of 6 months, and at 2-8 °C for a period of six months for solution and injections. ب _دراسة ثبات طويل الامد(Long Term Stability Testing)على درجة حرارة 30درجة مئوية ورطوبة نسبية 65% لفترة انتهاء عمر الدواء. Long Term Stability Testing at 30°C with relative humidity 65% for a period of end of the expiry date ج_تتضمن دراسات الثبات نتائج مواد التحطم والشوائب المعروفة وغير المعروفة بالاضافة الى المواد الحافظة ومواد منع اللتأكسد Stability Testing should determine degradation products known. and unknown impurities and Antioxidant 7_ دراسة فاعلية المواد الحافظة التي تستعل في المستحضرات السائلة واي مستحضر يحتوي على المواد الحافظة Study on the Preservative Efficacy Testing 8_ دراسة التثبت Process Validation على ثلاثة تشغيلات انتاجية 9- دراسة سمية المستحضر وموائمته او تضاده او تفاعله (Interaction) مع المستحضرات الاخرى ان وجدت والتحذيرات (Precautions) الخاصة بذلك. 10- دراسات الامان والمتبقيات (Residual and Safety Acceptable Level) والمستوى المسموح بها والفترة الزمنية المقترحة لذلك. 11- دراسات صيدلانية كاملة عن المستحضر وسلامتة المستحضر وتشمل: . التوافر الحيوي للمستحضرات الجديدة والتكافؤ الحيوي للمستحضرات (الجنيسة) التقليدية. Bioavailability study on the new products and bioequivalence for The Generic drug product. 12. المراجع العلمية ونتائج التجارب الميدانية References and field clinical studies ملحق رقم (3) الملف الاداري الرقـم : التـاريخ : نموذج طلب (تسجيل/ تجديد) دواء /لقاح عطوفة مدير البيطرة والصحة الحيوانية قسم الصيدلة والرقابة الدوائية أدرج أدناه المعلومات المطلوبة لتسجيل الدواء ، راجيا" التكرم بعرض طلبي على اللجنة الفنية لمراقبة الأدوية وإعلامي بقرارها. 1) طلب التسجيل : اسـم طالب التسجيل : 2) الـدواء : اسـم الـدواء :الشكل الصيدلاني: التعبئـة : العيـار : 3) الشركة الصانعة : اسم الشركة الصانعة : مركزها الرئيسي : عنوان الفرع المصدر للأردن : 4) السـعر : سعر التصدير للأردن ( فـوب / س . ف ) : السعر المقترح للصيدلي في الأردن: السعر المقترح للجمهور في الأردن : واقبلوا فائق احترامي خاتم المستودع اسـم المسـؤول : توقيعه : 5) الإجراءات المتخذة من قبل الدائرة : ساعة وصول الطلب : تاريخ ورود الطلب : رقم قيد الطلب ‍بسجلات اللجنة الفنية : الخاتم الرسمي إسم المستلم : توقيعــه : DRUG REGISTRATION FORM 1) DRUG: • NAME: • PHARMACEUTICAL FORM: • PACK SIZE: • STRENGTH: • PACK SIZES AND STRENGTHS USED IN THE COUNTRY OF ORIGIN: 2) MANUFACTURER: • NAME : • ADDRESS : • ADDRESS OF THE BRANCH SUPPLYING JORDAN WITH THIS DRUG : 3) PRICES: • EXPORT PRICE TO JORDAN ( FOB / C & F ) : • PRICE TO PHARMACIST IN THE COUNTRY OF ORIGIN : • PRICE TO PUBLIC IN THE COUNTRY OF ORIGIN: 4)COMPOSITION: A ) ACTIVE CONSTITUENTS (NAME AND QUANTITIES): B ) OTHER CONSTITUENTS: C ) OVERAGE: 5 )SOURCES OF ACTIVE CONSTITUENS: 6 )QUALITY CONTROL: 7 )CONTAINERS: (TYPES OF CONTAINERS USED FOR THE PACKAGED PRODUCT): 8) STABILITY AND SHELF - LIFE : • VALIDITY OF THE DATED PRODUCT : • ANTICIPATED SHELF LIFE OF OTHER PRODUCTS : • PHYSICAL CHANGES ANTICIPATED DURING STORAGE: • CHEMICAL CHANGES ANTICIPATED DURING STORAGE : 9) LABEL AND INSERTS : USES : PRECAUTIONS: FIRST AID : ANTIDOTE: SAFETY PERIOD : CLINICAL USE (USAGE) : 10)TOXICOLOGY ملحق رقم (4) CTDمتطلبات ملف تسجيل الدواء حسب تقدم المعلومات الواردة في هذا الملحق داخل ملف كرتوني مقوى أو مايشابهه يحمل اسم الدواء التجاري وشكله الصيدلاني واسم المادة الفعالة وتركيزها على غلافه الخارجي وعلى جانبه مطبوعا بالعربية والانجليزية ( Check List Regarding CTD Submission For Drug Registration Purposes ) Module 1 : Administrative Documents Section Cover letter 1.0 Comprehensive ( module 2-5 ) 1.1 Application forms 1.2 Check list 1.2.1 Drug registration form 1.2.2 Technical committee form 1.2.3 Computer application form 1.2.4 veterinary stability report form 1.2.5 Product information 1.3 SPC ( summary of product characteristic ) , labeling , package leaflet 1.3.1 Mock – up 1.3.2 Specimen ( one registration sample ) 1.3.3 Specific requirements for different types of applications 1.4 Information for application type ( generic , bio – similar ………..) 1.4.1 Information for submission type ( technology transfer, under license…… ) 1.4.2 Information related to pharmacovigilance : 1.5 Pharmacovigilance system 1.5.1 Risk – management system 1.5.2 Other information 1.6 List of similar product available in local market 1.6.1 Detailed comparison between generic leaflet & originator ( for generic drugs ) 1.6.2 Declaration from the manufacturer about the ingredient/s from human or animal origin included in the composition of the product and their source and the related certificates ( TSE CEP ) 1.6.3 List from manufacturer to declare the world wide registration status( registered / marketed ( date ) , under registration , rejected ( with reason) ) . 1.6.4 Technical contract / ( Open Part ) in case of contract manufacturing 1.6.5 Health authority approval of the latest plasma master file ( if the product contain plasma derivatives ) 1.6.6 Certificates 1.6.7 Certificate of pharmaceutical product ( CPP ) according to WHO format certificate and legalized 1.6.7.1 Sam PC certified and legalized from country of origin ( excluding generics ) . 1.6.7.2 Price certificates : ( for imported products ) ( pieced drug ) : - public price certificate showing price structure : ex. F. WSP ,pp , ( certified and legalized ) ; if vat included specify. - price structure from median countries. - export price letter for Jordan and export price to Saudi Arabia( if marketed ). 1.6.7.3 Price certificate: ( for local products ) suggested public price- pharmacist price or hospital price( for priced drug ) 1.6.7.4 Veterinary approval certificate for the manufacturing site/ s ( for the same production line) ( or copy of the request letter for approval( date and number) 1.6.7.5 a copy of veterinary department approval of the B. E or the comparative dissolution profile should be provided( for generic drugs. ) 1.6.7.6 Module 2 CTD summaries Section CTD table of contents ( Module 2-5 ) 2.1 CTD introduction 2.2 Quality Overall Summary 2.3 Drug product 3.2.p Description and composition of the drug product 3.2.p.1 Pharmaceutical development 3.2.p .2 Components of the drug product 3.2.p.2.1.1 Drug substance 3.2.p.2.1.2 Excipients 3.2.p.2.2 Drug product 3.2.p.2.2.1 Formulation development 3.2.p.2.2.2 Overages 3.2.p.2.2.3 Physiochemical and biological properties 3.2.p.2.3 Manufacturing process development 3.2.p.2.4 Container closure system 3.2.p.2.4 Microbiological attributes 3.2.p.2.5 Compatibility 3.2.p.2.6 Manufacture 3.2.p.3 Manufacturers( s) 3.2.p.3.1 Batch formula 3.2.p.3.2 Description of manufacturing process and process controls 3.2.p.3.3 Control of critical steps and intermediates 3.2.p.3.4 Process validation 3.2.p.3.5 Control of Excipients 3.2.p.4 Specifications 3.2.p.4.1 Analytical procedures 3.2.p.4.2 Validation of analytical procedures 3.2.p.4.3 Justification of specifications 3.2.p.4.4 Excipients of human or animal origin 3.2.p.4.5 Novel excipients 3.2.p.4.6 Control of drug product 3.2.p.5 Specification( s ) 3.2.p.5.1 Analytical procedures 3.2.p.5.2 Validation of analytical procedures 3.2.p.5.3 Batch analyses 3.2.p.5.4 Characterization of impurities 3.2.p.5.5 Justification of specification 3.2.p.5.6 Reference standards of materials 3.2.p.6 Container closure system 3.2.p.7 Stability : 3.2.p.8 Stability summary and conclusion 3.2.p.8.1 Post – approval stability protocol and stability commitments 3.2.p.8.2 Stability data 3.2.p.8.3 Real stability data 3.2.p.8.3.1 Accelerated stability 3.2.p.8.3.2 Regional information 3.2.R Certificate of analysis for drug substance from supplier/ s Certificate of analysis for drug substance from drug product manufactures COA should be stamped and signed or electronic signature ) ) 3.2.R.1 Valid certificate of suitability( CEP) from EDQM for drug substance( from each supplier) ( copy ) 3.2.R.2 valid GMP certificate for drug substance manufacturer( notarized copy) from each manufacturer only of CEP is not available( note that in this case all drug substance sections will be required) 3.2.R.3 Certificate of Analysis Of Finished Product Stamped And Signed Or Electronic Signature 3.2.R.4 In use stability according to dosage from( reconstitution inverted position , in use , etc ) 3.2.R.5 Photo stability( if needed) 3.2.R.6 Raw data and chromatograms for stability study and for validation 3.2.R.7 . Batch record for 3 consecutive production batches ( for biological products 3.2.R8. Latest plasma master file ( if the product contain , plasma , derivatives ) 3.2.R9.. CD ( electronic copy of technical file ) 3.2.R.10 Module 4 : non clinical study report Section Table of contents of module 4 4.1 Non clinical study reports 4.2 Pharmacology 4.2.1 Pharmacokinetics 4.2.2 Toxicology 4.2.3 ملحق رقم (5) Check list for vaccines PART I A: ADMINISTRATIVE DATA 1. NAME OF PRODUCT 2. PHARMACEUTICAL FORM 3. NAME AND ADDRESSES OF THE MANUFACTURER 4. NUMBER AND TITLES OF VOLUMES SUPPLIED IN SUPPORT OF APPLICATION 5. SAMPLE 6.LIST OF COUNTRIES WHICH HAVE AUTHORIZED THE PRODUCT. PART I B: SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCT 2. QUALITATIVE AND QUANTITATIVE COMPOSITION IN TERMS OF THE ACTIVE SUBSTANCES AND CONSTITUENTS. 3. PHARMACEUTICAL FORM 4. PHARMACEUTICAL PROPERTIES 5. CLINICAL PARTICULARS 6. PHARMACEUTICAL PARTICULARS 7. ADDITIONAL INFORMATION • TEXT OF THE LABEL • TEXT OF THE BOX • DIRECTION FOR USE (PACKAGE INSERT) PART II: ANALYTICAL DOCUMENTATION A: QUALITATIVE AND QUANTITATIVE COMPOSITION PARTICULARS OF THE CONSTITUENTS. B: COMPOSITION OF IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCT C: DESCRIPTION OF METHOD OF PREPARATION OF FINISHED PRODUCT D: FLOW CHART OF THE METHOD OF PREPARATION AND QUALITY CONTROL PROCEDURE. E: PRODUCTION AND CONTROL OF STARTING MATERIALS 1. STARTING MATERIALS LISTED IN PHARMACOPOEIA 2. STARTING MATERIALS NOT IN A PHARMACOPOEIA F : CONTROL TESTS DURING PRODUCTION G : CONTROL TESTS ON FINISHED PRODUCT H : STABILITY STUDY 1. MASTER SEED VIRUS (M.S.V) 2. QUALITY OF SPF EGGS 3. CERTIFICATES OF ANALYSIS OF THE FINISHED PRODUCT 4. CERTIFICATES OF ANALYSIS OF RAW MATERIALS 5. STABILITY REPORT ( ACCELERATED AND LONG TERM) PART III : SPECIFICATION OF PACKING GLASS CONTANIERS RUBBER STOPPERS PART IV : BIOLOGICAL TEST STERILITY TEST TEST FOR EXTRANEOUS AGENT TEST FOR EXGENIC LEUCOSIS TEST FOR MYCOPLASMA TEST FOR MICROBIAL CONTAMINATION PART V : SAFETY DOCUMENTATION A – SAFETY LABORATORY TESTS 1. SAFETY OF VACCINATION OF ONE DOSE 2.SAFETY OF VACCINATION OF AN OVER DOSE 3.SAFETY OF REPEATED VACCINATION OF ONE DOSE 4. EXAMINATION OF EGG PRODUCTION PERFORMANCE 5. EXAMINATION OF IMMUNOLOGICAL FUNCTIONS. 6. IMMUNO – SUPPRESSIVE SIGNS B – SAFETY FIELD STUDIES 1. SAFETY OF ADMINISTRATION OF ONE DOSE IN BROILERS 2. SAFETY OF ADMINISTRATION OF ONE DOSE IN BREEDERS PART IV: EFFICACY DOCUMENTATION A – EFFICACY LABORATORY TESTS 1. EFFICACY OF THE ADMINISTRATION OF ONE DOSE B – EFFICACY FIELD STUDIES 1. EFFICACY OF THE ADMINISTRATION OF ONE DOSE ملحق رقم (6) Check list for Pesticides 1- النشرة الفنية للمبيد تبين مواصفاته وتركيبته و سميته والجرعة المضادة و خواصه الكيماوية و الطبيعية وطريقة استعماله 2- أن تميز عبوة العينة بشكل واضح بأنها عينة للتجارب وغير مخصصة للبيع 3- يقدم طلب تسجيل معبأ من الشركة الصانعة للمبيد ومختوما بخاتمها المعتمد ومنسوخا على شريط ممغنط. 4- شهادة بأن الشركة مصدر المبيد شركة منتجة للمبيد أو مصنعة أو مجهزة له على أن تكون هذه الشهادة صادرة من الجهة الحكومية المختصة بتسجيل المبيدات في بلد المنشأ ومصدقة حسب الأصول و أن لا يكون قد مضى على صدورها أو تصديقها اكثر من سنة بتاريخ تقديمها او ان يكون مصدر المبيد من مصنع محلي مرخص بموجب تعليمات تصنيع المبيدات السارية المفعول والتي تخول المصنع المحلي صناعة المبيد المراد تسجيله. 5- شهادة بأن المبيد مسجل ومسموح باستعماله في بلد المنشأ بنفس مواصفات تركيبه المقدمة للتسجيل من حيث اسم المادة أو المواد الفعالة الداخلة في تركيبته و تراكيزها ونمط تصنيعه و الاسم التجاري للمبيد و الاسم العام له على أن تكون هذه الشهادة صادرة من الجهة الحكومية المختصة في بلد المنشأ مصدقة 6 - ملصقة بلد المنشأ مصدقة من الجهة الحكومية المختصة و أن لا يكون قد مضى على تصديقها اكثر من سنة بتاريخ تقديمها . وعلى ان تتضمن مايلي : 1 - اسم المبيد التجاري باللغتين العربية و الإنجليزية 2 - المادة أو المواد الفعالة وتراكيزها (وزن/وزن) او (وزن/حجم)مع ذكر الاسم العام باللغتين العربية و الإنجليزية 3 - حالة المبيد( نمط التصنيع) سائل , بودرة 4 - ثبات المبيد على درجات حموضة الماء المختلفة 5 - أسماء الحيوانات والآفات المستهدفة وطريقة ونسبة الاستعمال و فترة الأمان 6 - قابلية المبيد للمزج مع غيره من المبيدات. 7 - سميته على السمك والنحل. 8 - الكمية الصافية في العبوة. 9- رقم التشغيلة وتاريخ الصنع وتاريخ انتهاء المفعول أو تاريخ الصنع ومدة صلاحية المبيد من تاريخ الصنع على أن يكون التاريخ مختوما باللغة العربية أو الإنجليزية على الملصقة أو على العبوة وان يكون بالشهر والسنة 10 - بلد المنشأ و اسم الشركة الصانعة 11 - اسم المستورد المحلي وعنوانه 12 - الاحتياطات الواجب اتخاذها عند استعمال المبيد والجرعة المضادة والإسعافات الأولية في حالة التسمم بالمبيد. 13 - تحذيرا بالصورة التوضيحية المعتمدة من منظمة الصحة العالمية أو من منظمة الأغذية والزراعة للامم المتحدة على أن تتضمن في جميع الحالات عبارة(مادة سامة ) بشكل واضح يمكن تمييزه بسهولة 14- التحذيرات الواجب اتباعها 15 - شروط التخزين الآمنة بما في ذلك الإشارة إلى حفظ المبيد بعيدا عن متناول الأطفال 16 - طريقة التخلص من العبوات الفارغة بصورة آمنة 17- فترة الامان 18- طريقة الحفظ و درجة الحرارة 19- شهادة تحليل المبيد تثبت أن مكوناته مطابقة نوعا وكماً للمواد التي جهز منها وان تتضمن الشهادة الاسم التجاري للمبيد 7 - طريقة ( تحليل المبيد) و ( تحليل الأثر المتبقي) و ( تحليل المادة الفنية الفعالة) لأغراض فحص المطابقة بما يتناسب مع إمكانات مختبرات الوزارة أو أي مختبرات أخرى تعتمدها الوزارة 8- كتاب تفويض من الشركة الصانعة تسمح للشركة المحلية بتسجيل المبيد 9- أية معلومات تراها اللجنة ضرورية بخصوص تسجيل المبيد. 10- دراسات الثبات قصيرة الامد و طويلة الامد على ثلاث تشغيلات ملحق رقم (7) Company Booklet وزارة الزراعة مديرية البيطرة والصحة الحيوانية قسم الصيدلة والرقابة الدوائية Ministry of Agriculture Veterinary and Animal Health Department Pharmacy &Drug Control Department المعلومات المطلوبة من الشركات الدوائية الصانعة INFORMATION ABOUT DRUG MANUFACTURERS General information Name of company…… ………… Main Address…………. Name & Address of various working branches Inside country of origin Address Name 2-Outside country of origin Address Name Name and branch supplying the Jordanian market N.B if the branch supplying the Jordanian market is not the Mother Company, please fill separate application for the mother company. ………………………………………………………………………………………… Names and address of other companies or share in its activities in the field of drugs, what sort of relation. ………………………………………………………………………………………… Year of foundation……………… Registered annual capital……… Working annual capital (optional……………………………………….. Annual sales value (optional)………………… Commercial form…………………………………… Total number of employees……………………………… Names and formulas of its pharmaceutical preparations (N.B may be submitted separately). Are these preparations totally or partially manufactured by the firm itself? If partially manufactured what are these products, where manufactured and why? Research products produced by the firm itself during the last ten years? Other activities beside pharmaceutical manufacturing Name of countries where products are marketed Research Division Do you have research laboratories? Number of specialized personnel working in these research laboratories (excluding administrative) -Physicians/veterinarians…...........………………………. -Pharmacists……………...………............…………… -chemists…...........……………………………………… -Other……………...........………………………………… What research activities and trials carried by these laboratories? ……………………………………………...……………………………………………Do u own or have at your disposal Laboratories or Veterinary Centers for carrying out tests and experiments on your products? Address Name ……….........................................................................................................…………… Do you collaborate with universities or scientific veterinary centers in research fields; give details ………………………………………………………………………………………… What is the annual budget reserved for research and development ………………………………………………………………………………………… Number of square meters assigned for these laboratories ………………………………………………………………………………………… Production Division Origin of principal raw materials: -Self manufacturing …………………………………………… -Under license………………………………………………….. -Other sources…………………………………………………… Number of qualification of personal working in the division: ………………………………………………………..………………………………… Number of square meters assigned for production area: -4- Control laboratories Do you have control laboratories? -For testing raw materials …… -For in-process control………… -For testing final products… What type of laboratory tests you perform? -Physical-chemical tests …….........……… -Microbiological tests…………….........… -Pharmacological tests…………………..... -Other tests -Number and qualification of personal working in these labs. Do u resort to the aid of other laboratories for control purposes; name these labs. And indicate what sort of assistance. ………………………………………………………………………………………… Number of square meters assigned for these labs. ……………………………………………………………………… Give the details the activities performed by the competent authorities for controlling your establishment and its production. I the undersigned (full name of the person responsible for the establishment) Hereby declare that all the information given above is true, and I assume full responsibility for this Declaration with all consequences which might arise from false or erroneous information. Date Signature and stamp Legalization of the ministry of health or ministry of Agriculture or the official organization in charge of the control and inspection of pharmaceutical manufacturers that the information given above are correct. Legalization of the Jordanian consulate N.B. Please sign and stamp each page of this form ملحق رقم (8) التصنيع التعاقدي Contract Manufacturing هو قيام شركة دوائية تملك حق التصنيع أو التصنيع لمستحضر بالتعاقد مع شركة دوائية أخرى على تصنيع المستحضر كليا او جزئيا " من خلال القيام بإحدى خطوات التصنيع مثل (التعبئة والتغليف الأولي أو الثانوي أو إجازة التشغيلات). متطلبات تسجيل الأدوية التي تصنع تعاقديا : 1. تحديد الخطوات الرئيسة لعملية التصنيع و الموقع الذي تتم فيه كل خطوة . 2. نسخة موقعة من مانح العقد و منفذ العقد تتضمن البنود التالية والتي وردت في العقد الفني أ‌- الموافقة من منفذ العقد لمانح العقد على إمكانية التدقيق على مناطق الإنتاج و الرقابة والتخزين وطرق التصنيع والتحليل وسجلات التشغيلات و كافة الإمكانيات الفنية . ب‌- مسؤولية كل من مانح و منفذ العقد بما يتعلق بالخطوات التصنيعية والرقابية. ج- اسم الشخص المسؤول عن إجازة التشغيلات . د- مدة نفاذ العقد . 3. كتاب من الشركة مانحة العقد يفيد بمسؤولياتها عن الدواء . 4. تعهد الشركة مانحة العقد بإعلام المؤسسة عن أي تغيير بالمعلومات الواردة في البند 1و 2 وقبل البدء بالتغيير . 5. في حال الانتاج التعاقدي مع شركة محلية و تقديم خطة زمنية للانتقال إلى مرحلة التصنيع الكامل لدى المصنع المحلي فيتم منح الدواء الأولوية في التسجيل لتشجيع نقل التكنولوجيا . ملحق رقم (9) متطلبات تجديد التسجيل Re-Registration Drug Department Applicant Name: Application Type: Drug Name &Conc : Pack Size and Type : Re- Registion File Content:- PageN# YES/NO Module1:Administrative Part 1.A letter from the drug store or Technlcal manager of the local company declaring their request to re-register the drug 2. A letter from the drug product manufacturer/mah declaring their request for re-registration. 3.Lf1 (registration certificate)/Re-registration certificate. 4.application from ,filled and signed. Renewal application. 5. Fees for re –registration of additional packs Fees for any post – approval change . 6. comparison table between registration and re- registration files ( form) 7. re- registration & pricing committee decision forms 8. world – wide registration status of the drug. 9. list of ingredients of the drug that are of human or animal origin , and all related certificates. 10. approval letters for any post- registration changes. 11. confirmation letter from the manufacturer that there are no changes in manufacturing process, method of analysis ,formula, packaging material, specifications,…. Etc. if there is a change ,it should be submitted according to '' post approval change'' Guidance. 12. approval letters of finished product manufacturer 13. approval letters of API manufacturer, if the letter is not available, data for API approval should be submitted according to the PAC. 14. Updated technical agreement ( in case contract manufacturing ). 15. art work : inner label, outer pack , insert leaflet ( with revision date ) 16. for originator drug : legalized smPC from health authority in the country of origin. For generic drug : the insert leaflet should be similar to the originator, comparison table is required and copy of originator leaflet. 17. updated plasma master file for products containing ingredients of human plasma origin & the approval letters from health authority in country of origin 18. Certificates Pricing certificates of the drug in accordance with the adopted pricing a CPP from the country of origin issued by the competent authorities ( duly legalized) according to article (6) of registration criteria & the contents of WHO format . B Module 3 : Technical file Composition of drug (numbered , dated , and signed). Approved release and shelf-life specifications of the drug (numbered , dated , signed) Certificate of analysis of the finished product. Stability studies (taking into consideration that long term stability data from three production batches covering the proposed shelf life were available and submitted according to the commitment in registration files): ongoing stability study for at least one new production batch and its chromatograms. (initial and at end of shelf life) stability conclusion including the recommended storage conditions, shelf life , in the primary packaging.(which should be compatible with leaflet & outer pack information) 4. Mudule 5 : post marketing safety repots Most recent (PSUR) / safety update reports .