Incremental GMPs. Presented by: Karen S. Ginsbury For: IFF October 31, Nov 02, PCI Pharmaceutical Consulting Israel Ltd.

Transcription

1 Incremental GMPs Presented by: Karen S. Ginsbury For: IFF October 31, Nov 02, /55

2 Sound Science Good Development Practice Traceability R&D Tox I II III IV What You Need Here Can t be generated here 2/55

3 What are the Musts and When? Make a list of topics that need handling and discussing: the more you put down the better our discussion! 3/55

4 Recommendations for complying with CGMP Requirements - FDA Utilize appropriate quality control (QC) standards, i.e.: well defined procedures adequately controlled equipment accurate recording of all data Application of QC standards leads to implementation of CGMPs consistent with good scientific methodology 4

5 Annex 13 - Principle Procedures flexible to provide for changes as knowledge of the process increases, and appropriate to the stage of development of the product 5

6 Quality System - SOPs There is a need for a quality system in any functional organization A quality system means: Quality policy Management commitment CAPA system (of some description) Monitoring, evaluation and continual improvement activities 6

7 Process Performance and Product Quality Monitoring Through Lifecycle 7

8 Application of CAPA Through Lifecycle 8

9 Change Management Through Lifecycle 9

10 Management Review Through the Lifecycle 10

11 Recommendations for complying with CGMP Requirements (FDA) Use available technology and resources to facilitate product development, CGMP compliance, and lessen CGMP burden, i.e.: disposable equipment and process aids prepackaged water for injection (WFI) and sterilized containers contract manufacturing and testing facilities 11

12 Recommendations for complying with CGMP Requirements (FDA) Prevent contamination and crosscontamination: evaluate production environment to identify potential hazards ensure that substances (i.e. chemicals, adventitious agents) from previous or concurrent research or production are removed 12

13 General CGMP Requirements Personnel: education, experience and training, (or any combination of the three) to perform assigned functions, e.g. training to include GMPs outlined in guidance 13

14 Annex 13 - Principle Increased risk of product cross-contamination and mix up May be incomplete knowledge of potency and toxicity of product and a lack of full process validation Marketed products may be used which have been re-packaged or modified in some way Challenges require personnel with a thorough understanding of, and training in, the application of GMP to investigational medicinal products 14

15 General CGMP Requirements (FDA) Quality Control Function: established for every manufacturer of IND products responsibilities documented in writing and include: examination of components, containers, closures, inprocess materials, packaging and labeling materials review and approval of production and testing procedures, acceptance criteria review of completed production records for release or rejection of each clinical batch is responsibility of all staff involved in production in operations with limited staff QC function may be carried out by the same person performing production (with periodic review by another qualified person) 15

16 Annex 13 - Revision A minor change has been made to section 3 in order to reinforce the principle of independence between production and quality control functions in cases where the number of personnel involved is small All personnel involved with IMPs should be appropriately trained in the requirements specific to these types of product In cases where the number of staff involved is small, there should be, for each batch, separate people responsible for production and quality control 16

17 Batch Release Annex 13 The Qualified Person should be responsible for ensuring that there are systems in place that meet the requirements of this Annex and should therefore have a broad knowledge of pharmaceutical development and clinical trial processes 17

18 Batch Release Annex 13 IMPs should remain under control of the sponsor until after completion of a two-step procedure: certification by the Qualified Person and release by the sponsor for use in a clinical trial following fulfillment of the requirements of Article 9 (Commencement of a clinical trial) of Directive 2001/20/EC Both steps should be recorded and retained in the relevant trial files held by or on behalf of the sponsor The Sponsor should ensure that the details set out in the clinical trial application and considered by the Qualified Person are consistent with what is finally accepted by the Competent Authorities Arrangements should be established to meet this requirement e.g. through a change control process for the Product Specification File and defined in a Technical Agreement between the QP and the Sponsor 18

19 Batch Release Annex 13 batch records, including control reports, in-process test reports and release reports demonstrating compliance with the product specification file, the order, protocol and randomisation code include all deviations or planned changes, and any consequent additional checks or tests, and should be completed and endorsed by the staff authorised to do so according to the quality system production conditions; the validation status of facilities, processes and methods; examination of finished packs; where relevant, the results of any analyses or tests performed after importation; stability reports; the source and verification of conditions of storage and shipment; audit reports concerning the quality system of the manufacturer; Documents certifying that the manufacturer is authorised to manufacture investigational medicinal products or comparators for export by the appropriate authorities in the country of export; where relevant, regulatory requirements for marketing authorisation, GMP standards applicable and any official verification of GMP compliance; all other factors of which the QP is aware that are relevant to the quality of the batch 19

20 General CGMP Requirements (FDA) Facilities: adequate work areas for intended tasks water of appropriate source and quality adequate air handling to prevent contamination and cross-contamination 20

21 General CGMP Requirements (FDA) Equipment: in proper working condition, maintained calibrated, cleaned and sanitized at appropriate intervals appropriate for intended function should not contaminate or be reactive, additive or absorptive with product identified and documented in production records 21

22 General CGMP Requirements (cont d.) Control of Components: written procedures describing handling and control of components written, specified attributes or acceptance criteria COA or other documentation for components to ensure conformance with specified attributes records of receipt, quantity, supplier s name, lot number, expiration date 22

23 General CGMP Requirements (FDA) Production and Documentation: records including laboratory and production data detailing components, equipment and procedures used records of changes in processes and procedures appropriate microbiological control for production of sterile processed products 23

24 General CGMP Requirements (FDA) Laboratory Controls: tests conducted using established written procedures under controlled conditions scientifically sound analytical procedures properly calibrated and maintained analytical lab equipment initiate stability study to support use of product in clinical investigation 24

25 General CGMP Requirements (FDA) Container Closure and Labeling: Package to protect product from alteration, contamination and damage during storage, handling and shipping Controlled labeling to preclude mix-ups Distribution: Describes the transport of the IND product from the point of production to the patient/subject for consumption 25

26 General CGMP Requirements (FDA) Recordkeeping Retain records related to quality and operation of production processes including: Equipment maintenance and calibration Production records and related analytical test records Distribution records All quality control functions Component records Retain records for 2 years after approval of marketing application or until 2 years after shipment and delivery of the product is discontinued and FDA is notified 26

27 Multi-product Facilities An area or room can be used for multiple purposes and products, provided that: only one product is produced in an area at any given time appropriate cleaning and change over procedures are in place to ensure there is no carry-over of materials or products or mix-ups 27

28 Biological and Biotechnological Products Additional safeguards Some production systems may warrant additional safeguards to protect personnel (e.g., pathogenic microorganisms, some products made from spore-forming microorganisms, live viral vaccines and gene therapy vectors) Equipment qualification and controls in production assure success of unit operations with safety-related functions (e.g., viral clearance, virus/ toxin attenuation, pasteurization) 28

29 Biological and Biotechnological Products (cont d.) Retained samples (e.g., drug substance, drug product, intermediates) can be subsequently analyzed and compared to provide assurance of product consistency throughout clinical development. In-process testing and detailed records ensure product consistency for Phase 1 products which are produced in multiple lots 29

30 Sterile/Aseptically Processed Products Investigational products intended to be sterile require specific precautions, for example: personnel should be properly trained in aseptic techniques aseptic manipulation should be conducted in a Class 100 environment e.g. laminar flow hood controls should be in place to assure appropriate air quality of the aseptic environment 30

31 GMPs for Phase I A. Personnel B. Quality Function C. Facility & Equipment D. Component control E. Production & Documentation F. Laboratory controls G. Container closure & labelling H. Distribution I. Record-keeping 31/55

32 Points to Consider Aseptic processing: safety, needs to be right the first time i.e. for phase I BUT e.g. use of LAF hood for preparation in laboratory could be acceptable Viral safety.how much validation Minimization of cross-contamination Line clearance for packaging operations Analytical methods 32

33 Which Points Need Emphasis Responsibility and authority of Quality Unit (even where the function is shared with other duties) Clear definition of Quality System ISO or ISO-like? Personnel training and qualification Emphasis on resources outside the company Documentation 33

34 Which Points Need Emphasis Deviation reporting Change control and audit trail Written, signed off production documents Written, signed off analytical methods With version control Packaging Controls Batch Release 34

35 Purchasing Controls Written procedures describing: handling, review, and acceptance and control of components used in the production of an investigational product Components should be e.g. segregated, labeled, until examined or tested, as appropriate, and released for use in production Handle and store to prevent degradation or contamination Keep records of receipt and use Acceptance criteria, COAs and identity testing 35

36 Documentation Production records Laboratory records Deviation reporting Change: control and audit trails Batch release records 36

37 Packaging Controls May be particularly complex for clinical trials because of placebo Make sure no previous product Avoid mix-ups Document line clearance 37

38 Quality Assurance: Definition 2003/94/EC pharmaceutical quality assurance means the total sum of the organised arrangements made with the object of ensuring that medicinal products or investigational medicinal products are of the quality required for their intended use 38

39 R & D Bench top Batches - Problems Do we record material usage (reconciliation)? Do we use released materials? If no, do we audit suppliers before selecting materials? At least by mail? Do we assess more than one supplier? 39

40 R & D Bench top Batches - Problems -2 Do we consider cross-contamination? Do we calibrate equipment? Do we validate equipment? How much documentation do we need? How many signatures for each step? What about packaging materials? What about stability? Etc.etc.etc. 40

41 Reducing the Variables Man Machines Materials Methods training, procedures Use identical equipment Document material suppliers, lot #, exp. date Detailed, documented procedures, performed the same way 41

42 Good Documentation Practice Entries made at time of action Entries initialized and dated by the person entering the data Entries legible, in clear handwriting Raw data shall be unequivocal Never discard original raw data Never use correction fluid or tape Use indelible, water-resistant blue or red ballpoint pen/document pen Raw data generated on thermo-sensitive paper shall be photocopied onto a durable medium Sufficient space for entries Any alteration to an entry shall be corrected by a single line through the original data leaving the original entry still readable. Initialize and date preferably by the original person entering the data. When appropriate, the reason for the alteration shall be recorded Unusual observations recorded signed and dated Entries in chronological order When transferring data, reference the original data Transferring of data checked by a second person Avoid entries like OK or complies/not complies Calculations documented Unused empty fields crossed-out by a single diagonal line or by N/A entries { } and repeat signs ( ) shall not be used Agree on date format Attachments consecutively numbered and referenced to the relevant document Entries reviewed for accuracy and completeness by a second person Never use glue or tape, always staples Never start an experiment without a plan 42/55

43 Raw Data Original worksheets calibration data records memoranda and notes of firsthand observations Activities of a study needed for reconstruction /evaluation of the study. 43

44 Raw Data cont/ Raw data may include, but are not limited to photographic materials, magnetic, electronic or optical media information recorded from automated instruments, and hand recorde datasheets. Facsimile transmissions and transcribed data are not considered raw data. 44

45 Data Collection Need: Pre-established systematic written procedures for the organization, conduct, data collection, documentation and verification of studies To assure validity of data ethical, scientific and technical quality of studies commercial viability 45

46 Follow written procedures Data collected from studies designed, conducted, monitored, recorded, audited, analyzed and reported in accordance with pre-established written procedures can be expected to facilitate the review process since the regulatory authorities can have confidence in the integrity of studies which follow such procedures 46

47 Analytical Methods Assay development. Specification setting and tightening. Assay validation and transfer to QC. At what stage of the game? 47

48 Methods Development Start by basing your test on a previous test or on a pharmacopeial monograph or on an official source or on a reference article May make handwritten changes: BUT need documentation Then have version 01 of computerized document BUT do you have documentation control 48

49 Methods Development - 2 Then formulators make a change that they forget to tell you about So you have artifacts and After finally sitting down with them, you have to revise the method BUT: did you document this? Because they will change it again and then you may want to go back to version 01! 49

50 Methods Development Report - 3 Write what failed as well as what succeeded QC will try to revise method and you may save them a lot of time by showing in the report that their improvements do not work for this product Conclude with validation results Don t forget stability and stability indicating methods 50

51 Outsourcing קבלנות משנה Proof of concept, pre-clinical, clinical studies all require the use of outside contractors There is a wide selection all over the world Some have more experience, some less There is NO approved laboratory - FDA does not hand out approvals - only disapproval 51

52 Outsourcing -2 The contractor is only as good as the client they are working with Use laboratories to perform analytical and micro testing: if you have no in-house knowledge you are relying solely on the laboratory as a consultant: they are an interested party! Use manufacturing facilities which if they fail inspection will down your company 52

53 Outsourcing -3 Contractors are quick to pick up on who the client is All requests in writing Signed quality contract that addresses responsibilities: Contract manufacturers GMP Meet face to face Where possible choose close to home (easier to audit) 53

54 Thank you for your attention Questions? 54