Incremental GMPs for IMPs and QP Batch Certification Presented by: Karen S. Ginsbury For: IFF October 2009 PCI Pharmaceutical Consulting Israel Ltd.
Course Objective Provide an overview of regulations and expectations of regulatory authorities regarding manufacture and in particular, certification and release of clinical trials material PCI Pharmaceutical Consulting Israel Ltd.
To be discussed… • EU + US legislation / guidance for IMPs: – FDA’s GMPs for Phase I guidance – EU Annex 13 • The role of the Quality Unit vs The Qualified Person in batch certification and / or release (Annex 16) • Sponsor responsibilities and release to sites • Documentation requirements – Product Specification File • Contract manufacture and analysis of investigational products PCI Pharmaceutical Consulting Israel Ltd.
To be discussed… • • • Preliminary Hazard Analysis / risk assessment tool for determining GMP levels Pre-clinical batches: “GMP” or not Risks for early / late phase: – Analytical methods qualification / verification / validation – Cleaning verification / validation – Facilities: dedicated / campaign basis / potent drugs /biological – Vendors: qualification / approval program / auditing – at what stage • Process: - when to • define target product profile • identify Critical Process Parameters • identify Critical Quality Attributes start to show reproducibility think about validation packaging stability and retest / reuse/ expiry date PCI Pharmaceutical Consulting Israel Ltd.
The Playing Field FDA • Exempt phase I product from 21 CFR part 211 • Continue to oversee under STATUTORY requirements of FD&C Act • Phase 2 and 3 still under CFR EU Require ALL of GMP + Annex 13 + Annex 16 (QP release) For all phases PCI Pharmaceutical Consulting Israel Ltd.
Product Control Strategy and Risk Management • • Developing a Target Product Profile Product Specification File Initial risk assessment Company Strategy for controlling material to be used to generate data for use in regulatory submissions: pre-clinical toxicology, phase 1 – 3 • Product specific control strategy PCI Pharmaceutical Consulting Israel Ltd.
The Phases of Drug Development • Pre-Clinical • Toxicology, animals • Phase 1 • Safety in humans (usually first in humans) • Phase 2 • Small scale efficacy • Phase 3 • Large scale trial • Phase 4 • Post marketing PCI Pharmaceutical Consulting Israel Ltd.
Regulation of Clinical Trials Material US FDA EU EMEA • Investigational Medicinal • Investigational New Product Dossier (IMPD) / Drug Application (IND) • May “choose” to inspect Clinical Trial Application (CTA) generally based on IND • Obliged to inspect under clinical trial directive review (in third country this might be a • Very rare for FDA to QP audit rather than inspect even in phase 3 competent authority) • Inspections are common PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd. 9/48
IND Phase 1 – CMC Requirements • Drug Substance – Description (physical, chemical, biological) – Manufacturer (name and address) – Method of Preparation (brief description/ flow diagram, reagents, solvents, catalysts) – Analytical Methods ( brief description, proposed criteria, certificates of analysis) – Stability (brief description of study/test methods, preliminary tabular data) PCI Pharmaceutical Consulting Israel Ltd.
IND Phase 1 – CMC Requirements • Drug Product – Components (grade (e. g. USP/ NF, ACS), novel excipients, etc. ) – Quantitative composition – Manufacturer (name and address) – Method of Manufacture (narrative and/or flow diagrams, sterilization process for sterile products) – Analytical Methods • brief description of test methods and limits (dosage form dependent) – Stability of Drug product • Information to assure the product’s stability during the planned clinical studies PCI Pharmaceutical Consulting Israel Ltd.
IND Phase 1 – CMC Requirements • Placebo (NOTE: EU wants placebo / comparator product released by QP) – Description – Composition and Controls – Control PCI Pharmaceutical Consulting Israel Ltd.
FD&C Act • 501(a)(2)(B) requires all drug products be manufactured in accordance with current good manufacturing practice (CGMP) • CGMP Regulations, published in 1978 and codified in 21 CFR 210 and 211 primarily directed to commercial manufacturing of approved drugs and biologics PCI Pharmaceutical Consulting Israel Ltd.
General CGMP Requirements Quality Control Function: – established for every manufacturer of IND products – responsibilities documented in writing and include: • examination of components, containers, closures, in-process 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 PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
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) PCI Pharmaceutical Consulting Israel Ltd.
FDA Guidance, July 2008 PCI Pharmaceutical Consulting Israel Ltd.
GMP for Phase I A. B. C. D. E. Personnel QC Function Facility & Equipment Component control Manufacturing and Records F. Laboratory controls G. Packaging, Labeling, distribution H. Record-keeping PCI Pharmaceutical Consulting Israel Ltd.
EU Clinical Trials Directive 2001/20/EC • Laws, regulations relating to implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use (12) The principles of good manufacturing practice should be applied to investigational medicinal products. PCI Pharmaceutical Consulting Israel Ltd.
EU Clinical Trials Directive - 2 2001/20/EC 3. Take all appropriate measures to ensure that the qualified person is responsible for ensuring: – (b) in the case of investigational medicinal products manufactured in a third country, that each production batch has been manufactured and checked in accordance with: • standards of good manufacturing practice • product specification file • The clinical trial authorisation (CTA) PCI Pharmaceutical Consulting Israel Ltd.
EU Clinical Trials Directive – 3: Article 15 Verification of compliance of investigational medicinal products with good clinical and manufacturing practice • Member States shall appoint inspectors to inspect: – the trial site or sites – the manufacturing site of the investigational medicinal product – any laboratory used for analyses in the clinical trial – and/or the sponsor's premises. PCI Pharmaceutical Consulting Israel Ltd.
EU Clinical Trials Directive – 4: Article 15 Verification of compliance of investigational medicinal products with good clinical and manufacturing practice 4. The Commission, upon receipt of a reasoned request from a Member State or on its own initiative may propose that the trial site and/or the sponsor's premises and/or the manufacturer established in a third country undergo an inspection. The inspection shall be carried out by duly qualified Community inspectors. PCI Pharmaceutical Consulting Israel Ltd.
The meaning of the Directive • As of 01 May 2004 all manufacturers of IMPs including Phase 1 are open to inspection • QPs need to demonstrate competence and have required qualifications to certify (NOT release) IMPs PCI Pharmaceutical Consulting Israel Ltd.
The meaning of the Directive – 3 Voluntary Inspection Findings • Voluntary inspections ceased 01/05/04 • Findings: – Poorly developed quality systems – Inadequate facilities – Inadequate validation – Poorly defined QP responsibilities – Poor labeling / packaging practices – Poor TSE / BSE management PCI Pharmaceutical Consulting Israel Ltd.
EU GMP Directive 2003/94/EC • Principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use • “investigational medicinal product” appears 27 times PCI Pharmaceutical Consulting Israel Ltd.
Importer’s Responsibility 2003/94/EC • For … investigational medicinal products imported from third countries • the importer shall ensure that: – products have been manufactured in accordance with standards equivalent to the good manufacturing practice standards laid down by the Community – by a manufacturer notified to the competent authorities and accepted by them for that purpose. PCI Pharmaceutical Consulting Israel Ltd.
Manufacturer’s Responsibility - 3 2003/94/EC • Appropriate technical or organisational measures shall be taken to avoid cross contamination and mix-ups. • In the case of investigational medicinal products, particular attention shall be paid to the handling of products during and after any blinding operation. PCI Pharmaceutical Consulting Israel Ltd.
Manufacturer’s Responsibility - 4 2003/94/EC • For investigational medicinal products, the manufacturing process shall be validated in its entirety in so far as is appropriate: • taking into account the stage of product development • At least the critical process steps, such as sterilisation, shall be validated • All steps in the design and development of the manufacturing process shall be fully documented. PCI Pharmaceutical Consulting Israel Ltd.
Quality Control 2003/94/EC • For investigational medicinal products, the sponsor shall ensure that the contract laboratory complies with the content of the request referred to in Article 9(2) of Directive 2001/20/EC, as accepted by the competent authority. • When the products are imported from third countries, analytical control shall not be mandatory. PCI Pharmaceutical Consulting Israel Ltd.
Quality Assurance / Batch Release 2003/94/EC • During the final control of the finished product before its release. . for use in clinical trials, the quality control system shall take into account, in addition to analytical results, essential information such as the production conditions, the results of in-process controls, the examination of the manufacturing documents and the conformity of the product to its specifications, including the final finished pack. PCI Pharmaceutical Consulting Israel Ltd.
Annex 16 PCI Pharmaceutical Consulting Israel Ltd.
Scope of Annex 16 • This annex …gives guidance on the certification by a Qualified Person (QP) and • batch release within the European Community (EC) or European Economic Area • (EEA) of medicinal products holding a marketing authorisation or made for export. • The relevant legislative requirements are contained in Article 51 of Directive 2001/83/EC or Article 55 of Directive 2001/82/EC PCI Pharmaceutical Consulting Israel Ltd.
Annex 16 • Certification of the finished product batch: the certification in a register or equivalent document by a Q. P. , as defined in Article 51 of Directive 2001/83/EC and Article 55 of Directive 2001/82/EC, before a batch is released for sale or distribution. PCI Pharmaceutical Consulting Israel Ltd.
Batch Release Certificate PCI Pharmaceutical Consulting Israel Ltd.
Batch Release Certificate • Investigational Medicinal Products may not be used in a clinical trial in the EEA until completion of a two-step release procedure. The first step is the certification by the Qualified Person of the manufacturer or importer that the provisions of Article 13(a), (b) or (c) of Directive 2001/20/EC have been complied with. insofar as these provisions have been complied with, the IMPs in question shall not have to undergo any further checks if they move into another Member State provided they are accompanied by batch release certification signed by the Qualified Person. • The GCP and GMP Inspection Services of the Member States have agreed that the content of these certificates should be in accordance with the attached format PCI Pharmaceutical Consulting Israel Ltd.
Batch Release Certificate PCI Pharmaceutical Consulting Israel Ltd.
Batch Release Certificate PCI Pharmaceutical Consulting Israel Ltd.
Annex 16 • The annex covers in particular those cases where a batch has had different stages of production or testing conducted at different locations or by different manufacturers, and where an intermediate or bulk production batch is divided into more than one finished product batch • It also covers the release of batches which have been imported to the EC/EEA both when there is and is not a mutual recognition agreement between the Community and the third country • The guidance may also be applied to investigational medicinal products, subject to any difference in the legal provisions and more specific guidance in Annex 13 to the Guide PCI Pharmaceutical Consulting Israel Ltd.
Annex 16 • The basic arrangements for batch release for a product are defined by its Marketing Authorisation • Nothing in this annex should be taken as overriding those arrangements PCI Pharmaceutical Consulting Israel Ltd.
Annex 16 • Each batch of finished product must be certified by a QP within the EC/EEA before being released for sale or supply in the EC/EEA or for export PCI Pharmaceutical Consulting Israel Ltd.
Annex 16 The purpose of controlling batch release in this way is • to ensure the batch was manufactured and checked in accordance with: – Its marketing authorisation – the principles and guidelines of EC Good Manufacturing Practice or the good manufacturing practice of a third country recognised as equivalent under a mutual recognition agreement and any other relevant legal requirement before it is placed on the market and – in the event that a defect needs to be investigated or a batch recalled, to ensure that the QP who certified the batch and the relevant records is readily identifiable PCI Pharmaceutical Consulting Israel Ltd.
Annex 16 • in an industrial situation it is usually not possible for a single QP to be closely involved with every stage of manufacture • The Q. P. who certifies a finished product batch may need therefore to rely in part on the advice and decisions of others • Before doing so he should ensure that this reliance is well founded, either from personal knowledge or from the confirmation by other QPs within a quality system which he has accepted PCI Pharmaceutical Consulting Israel Ltd.
Annex 16 • When some stages of manufacture occur in a third country it is still a requirement that production and testing are in accordance with the marketing authorisation, that the manufacturer is authorised according to the laws of the country concerned and that manufacture follows good manufacturing practices at least equivalent to those of the EC PCI Pharmaceutical Consulting Israel Ltd.
Annex 16 • the correct manufacture of a particular batch of product, regardless of how many sites are involved, should be the overall concern of the Q. P. who certifies the finished product batch before release PCI Pharmaceutical Consulting Israel Ltd.
Annex 16 • Different batches of a product may be manufactured or imported and released at different sites in the EC/EEA. For example a Community marketing authorisation may name batch release sites in more than one member state, and a national authorisation may also name more than one release site • In this situation the holder of the marketing authorisation and each site authorised to release batches of the product should be able to identify the site at which any particular batch has been released and the QP responsible for certifying the batch PCI Pharmaceutical Consulting Israel Ltd.
Annex 16 • The Q. P. who certifies a finished product batch before release may do so based on personal knowledge of all the facilities and procedures employed, the expertise of the persons concerned and of the quality system within which they operate. • Alternatively he may rely on the confirmation by one or more other QPs of the compliance of intermediate stages of manufacture within a quality system which he has accepted. • This confirmation by other QPs should be documented and should identify clearly the matters which have been confirmed • The systematic arrangements to achieve this should be defined in a written agreement in conformance with Chapter 7 (Technical Agreement / Quality Contract) PCI Pharmaceutical Consulting Israel Ltd.
Annex 16 • The agreement should include an obligation on the part of the provider of a bulk or intermediate product to notify the recipient(s) of any deviations, out-ofspecification results, non-compliance with GMP, investigations, complaints or other matters which should be taken into account by the QP responsible for certifying the finished product batch PCI Pharmaceutical Consulting Israel Ltd.
Annex 16 • For assembly at different sites under a single marketing authorisation, there should be one person, normally a QP of the manufacturer of the bulk production batch, with overall responsibility for all released finished product batchesderived from one bulk production batch • The duty of this person is to be aware of any quality problems reported on any of the finished product batches and to co-ordinate any necessary action arising from a problem with the bulk batch. • While the batch numbers of the bulk and finished product batches are not necessarily the same, there should be a documented link between the two numbers so that an audit trail can be established PCI Pharmaceutical Consulting Israel Ltd.
Annex 16 • QC laboratories authorised under separate marketing authorisation – QP must either take responsibility or have alternative QP assigned as responsible for testing and test results and their sign off • Same for third country manufacture (“equivalent” GMP) PCI Pharmaceutical Consulting Israel Ltd.
Annex 16 • Routine duties of QP prior to batch certification: – Compliance with MA – Compliance with GMP – Manufacturing and testing processes validated – Deviations / planned changes and notification of CA if needed – Documentation complete – Audits performed – QP’s knowledge up to date PCI Pharmaceutical Consulting Israel Ltd.
Retained Samples 2003/94/EC • For an investigational medicinal product, sufficient samples of each batch of bulk formulated product and of key packaging components used for each finished product batch shall be retained for at least two years after completion or formal discontinuation of the last clinical trial in which the batch was used, whichever period is the longer [Normally keep whole batch forever] PCI Pharmaceutical Consulting Israel Ltd.
Complaints 2003/94/EC • In the case of investigational medicinal products, the manufacturer shall, in cooperation with the sponsor, implement a system for recording and reviewing complaints together with an effective system for recalling promptly and at any time investigational medicinal products which have already entered the distribution network. PCI Pharmaceutical Consulting Israel Ltd.
Labelling 2003/94/EC • In the case of an investigational medicinal product, labelling shall be such as to: – ensure protection of the subject and traceability – enable identification of the product and trial – facilitate proper use of the investigational medicinal product. PCI Pharmaceutical Consulting Israel Ltd.
Annex 13 – July 2003 Manufacture of IMPs • Investigational medicinal products should be produced in accordance with the principles and the detailed guidelines of Good Manufacturing Practice for Medicinal Products (The Rules Governing Medicinal Products in The European Community, Volume IV) • [Rules to be found by entering: Eudra. Lex Volume 4 in search engine] PCI Pharmaceutical Consulting Israel Ltd.
Annex 13 cont/ • Packaging and Labeling. Self inspection or independent audits should be used to monitor these critical operations. • Personnel - separate QA and production (FDA also require this). • Batch release by qualified person (QP) PCI Pharmaceutical Consulting Israel Ltd.
Annex 13 cont/ • Product Specification File • A reference file containing, or referring to files containing, all the information necessary to draft the detailed written instructions on processing, packaging, quality control testing, batch release and shipping of an investigational medicinal product – constantly updated – QP needs to be familiar with it prior to certification PCI Pharmaceutical Consulting Israel Ltd.
Annex 13 cont/ 44. Investigational medicinal products should remain under the control of the Sponsor until after completion of a two-step release procedure: – certification by the Qualified Person – release following fulfilment of the requirements of Article 9 (Commencement of a clinical trial) of Directive 2001/20/EC – The sponsor should ensure that these are consistent with the details actually considered by the Qualified Person – Both releases should be recorded and retained in the relevant trial files held by or on behalf of the sponsor PCI Pharmaceutical Consulting Israel Ltd.
Annex 13 cont/ • Manufacturing and Packaging Records • Production – Starting materials should be well defined and documented. – Written procedures for generating randomization codes and blinding. • QC. • Complaints, returns, recalls, destruction. PCI Pharmaceutical Consulting Israel Ltd.
ICH Quality Vision (July 2003) Q 8, Q 9, Q 10 – The Trilogy “Develop a harmonized pharmaceutical quality system applicable across the life cycle of the product emphasizing an integrated approach to quality risk management and science. ” PCI Pharmaceutical Consulting Israel Ltd PCIPharmaceutical. Consulting Israel Ltd.
Definitions: Target Product Profile • A target product profile is a prospective and dynamic summary of the quality characteristics of a drug product that ideally will be achieved to ensure that the desired quality, and hence the safety and efficacy, of a drug product is realised • The target product profile forms the basis of design for the development of the product PCI Pharmaceutical Consulting Israel Ltd 80/60 PCIPharmaceutical. Consulting Israel Ltd.
Quality Attribute Target Route of administration Oral Dosage form Capsule, size 2, maximum fill weight 280 mg Strength 0. 6 mg Packaging Securitainer, plastic cap and alu overseal, dessicant Stability 3 yrs at room temperature Pharmacokinetics Immediate release enabling tmax in 2 hours or less Appearance White opaque cap and body, hard gelatin capsule filled with white to off-white granulate Assay 90 -110% Impurities Impurity A: NMT 0. 5%, Impurity B: NMT 0. 5% Total Impurities: NMT 2% Content Uniformity Meets USP Dissolution NLT 70% of labeled amount is dissolved in 30 min : (500 ml water; USP apparatus II {paddles}; 50 rpm) Microbiology PCI Pharmaceutical Consulting Meets USP criteria (NMT 1000 cfu /g; 100 cfu fungi) Israel Ltd.
Control Strategy: Definition • A planned set of controls, derived from current product and process understanding, that assures process performance and product quality • The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control (ICH Q 10) PCI Pharmaceutical Consulting Israel Ltd 80/62 PCIPharmaceutical. Consulting Israel Ltd.
Definitions Critical Quality Attribute (CQA): • A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality Critical Process Parameter: • A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality PCI Pharmaceutical Consulting Israel Ltd 80/63 PCIPharmaceutical. Consulting Israel Ltd.
Control Parameters vs CQAs Process Control Parameters – Risk assessment can be used to identify material attributes and process parameters that can affect CQAs – Risk assessment tools can be used to identify and rank parameters (e. g. , operational, equipment, input material) with potential to have an impact on product quality based on prior knowledge and initial experimental data – Batch production records are developed with paramter ranges designed to ensure the CQAs are achieved Critical Quality Attributes – physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality – CQAs are generally associated with the drug substance, excipients, intermediates, and drug product – Drug product CQAs include the properties that impart the desired quality, safety, and efficacy PCI Pharmaceutical Consulting Israel Ltd PCIPharmaceutical. Consulting Israel Ltd.
Product Specification File – Annex 13 • Should be continually updated during development to allow traceability to previous versions (audit trail) • Includes (but not necessarily limited to): – Specifications and analytical methods for starting materials, packaging materials – intermediate, bulk and finished product – Manufacturing methods – In-process testing and methods – Approved label copy – Relevant clinical trial protocols and randomisation codes – Relevant technical agreements with contract givers – Stability data – Storage and shipment conditions PCI Pharmaceutical Consulting Israel Ltd.
Product Specification File – Annex 13 • The contents will vary depending on the product and stage of development • The information should form the basis for assessment of the suitability for certification and release of a particular batch by the Qualified Person and should therefore be accessible to him/her • Where different manufacturing steps are carried out at different locations under the responsibility of different • Qualified Persons, it is acceptable to maintain separate files limited to information of relevance to the activities at the respective locations PCI Pharmaceutical Consulting Israel Ltd.
Risk Assessment in R&D: Control Parameters Ishikawa (Fishbone) Diagram PCI Pharmaceutical Consulting Israel Ltd 80/67 PCIPharmaceutical. Consulting Israel Ltd.
Q 8 R 1: Risk Management in R&D • A cross-functional team of experts could work together to develop an Ishikawa (fishbone) diagram that identifies all potential variables which can have an impact on the desired quality attribute • The team could then rank the variables based on probability, severity, and detectability using failure mode effect analysis • (FMEA) or similar tools based on prior knowledge and initial experimental data • Design of experiments or other experimental approaches could then be used to evaluate the impact of the higher ranked variables, to gain greater understanding of the process, and to develop a proper control strategy PCI Pharmaceutical Consulting Israel Ltd 80/68 PCIPharmaceutical. Consulting Israel Ltd.
Control Strategy • Controls should be based on product, formulation and process understanding and should include, at a minimum, control of the critical parameters and attributes • A comprehensive pharmaceutical development approach will generate process and formulation understanding that identifies sources of variability • Critical sources of variability that can lead to product failures should be identified, appropriately understood, managed or controlled PCI Pharmaceutical Consulting Israel Ltd 80/69 PCIPharmaceutical. Consulting Israel Ltd.
Control Strategy • Understanding sources of variability and their impact on downstream processes or processing, intermediate products and finished product quality can provide flexibility for shifting of controls upstream and • minimise the need for end product testing • Control of process parameters allows variability of raw materials to be compensated for in an adaptable process to deliver consistent product quality PCI Pharmaceutical Consulting Israel Ltd 80/70 PCIPharmaceutical. Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
Process Performance and Product Quality Monitoring Through Lifecycle PCI Pharmaceutical Consulting Israel Ltd.
Application of CAPA Through Lifecycle PCI Pharmaceutical Consulting Israel Ltd.
Change Management Through Lifecycle PCI Pharmaceutical Consulting Israel Ltd.
Management Review Through the Lifecycle PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
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 PCI Pharmaceutical Consulting Israel Ltd.
Contractors • Don’t forget that a lot of work is outsourced • Quality Agreements / Technical contracts are essential – with checklists • Batch release should always be based on a checklist to ensure relevant documentation is reviewed • Procedures in Quality Agreement re: recalls, complaints and especially for comparator and placebo PCI Pharmaceutical Consulting Israel Ltd.
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