The scope of the guideline is to provide guidance on the data to be included in a regulatory submission to demonstrate that the active substance manufacturing process is in a validated state. The guideline focuses on recombinant proteins and polypeptides, their derivates, and products of which they are components (e.g. conjugates). But it is explicitly mentioned that the principles could also be applied to vaccines or plasma-derived products and other biological products, as appropriate.
Process validation is mentioned as life cycle, comparable to Annex 15 and to the EMA guideline on process validation for finished products . Also comparable to both, the guideline offers a traditional or an enhanced (with reference to ICH Q 11) approach to process validation. A combination of both approaches is possible as well. This “hybrid approach” is in line with the other new European process validation guidelines, too.
Process validation is divided into two parts:
process characterisation, where the commercial manufacturing process is defined
process verification, where the final manufacturing process as established based on process evaluation studies performs effectively in routine manufacturing.
Process characterisation itsself is also divided into two parts:
process development, which includes studies to reach a potential design of a future manufacturing process
process evaluation which includes studies on small and/or commercial scales, providing evidence that the complete manufacturing process has been appropriately designed to design the full operating ranges of the manufacturing process.
It is explicitly mentioned that subsequent to succesfull process validation product quality and process performance must be maintained in a state of control during routine production. This ongoing process verification is normally not part of submission data, with the exception of e.g. niche products, which could not be fully validated at the time of the regulatory submission.
There is no number of validation runs mentioned in this guideline and concurrent validation could be considered only in exceptional circumstances (e.g. medical need is mentioned) and after consultation with the regulatory authorities.
EudraGMDP is the central database for GMP and GDP compliance. Inspections which have been performed by any of the EU member state inspectorates are published in the database. If the manufacturing or distribution site has been found in compliance with GMP and or GDP then a certificate is issued in the database as reference for other inspectorates. This information is also available to the public. A negative outcome will lead to a GMP or GDP Non-Compliance Report. In 2016 no GDP Non-Compliance Reports have been published until today but already 13 GMP Non-Compliance Reports until March 15th.
Among the companies concerned there are 5 Chinese, 3 French, 2 Spanish manufacturers as well as one each from Sweden, Romania and Poland. All Non-Compliance Report were either issued in 2016 (12) or updated in 2016 (1).
The GMP non compliance findings reveal severe deviations from EU GMP. In addition some companies are involved in falsification and data manipulations – a serious trend which can be observed in many international inspections (e.g. those performed by FDA, WHO). Data Integrity and falsification issues are highlighted in the findings below.
MINSHENG GROUP SHAOXING PHARMACEUTICAL CO. LTD, China
Overall, 18 deficiencies were observed during the inspection, including 2 Critical and 4 Major deficiencies: [Critical 1]Falsification of source of API (Thiamphenicol): Repackaging, relabeling and selling of purchased API from a non-GMP company (Zhejiang Runkang Pharmaceutical Co.Ltd.) as if manufactured in-house; [Critical 2] Praziquantel manufactured according to CP process/grade was released as USP process/grade without a full traceability of the testing activities ; [Major 1] The maintenance and the cleaning operations of the manufacturing line used for the production of Praziquantel (API) were found deficient; [Major 2] The pipes design of some equipment used for the manufacturing of Praziquantel, the handling of change related to these equipment and the instruction used for the transfer of the intermediate solution using nitrogen were found deficient ; [Major 3] The hoses used for unloading of solvent were not identified, had no cleaning status and were stored on a dirty floor of an area not mentioned in the general layout of the site; [Major 4] There was no procedure in place for audit trail and there was no effective audit trail in place to determine any change or deletion of the chromatographic raw data. The audit trial function including the administrator profiles was enabled for all the QC staff.
DESARROLLOS FARMACÉUTICOS BAJO ARAGÓN, S.L., Spain
The manufacturer has not established a quality management system including adequate controls to ensure the accuracy and completeness of the critical records data.
S.C. IRCON SRL, Romania
During inspection a number of 34 deficiencies were found, out of which 4 were critical and 10 major. Critical deficiencies are related to the quality management system, qualification/validation activities, manufacturing and material management documents and quality control laboratories activity.
Agila Specialties Polska Sp. z o.o, Poland
29 major deficiencies were found in Agila Specialties which pose a risk of microbial and particulate contamination and could not assure the sterility of the final product. Most of these are related to: 1.) design and qualification of HVAC, laminar air flow system and clean areas, 2.) cleaning and maintenance of clean areas. 3.) manufacturing and batch releasing in the conditions not complying with GMP requirements 4.) change control. In December, 2014 the HVAC system of vials and prefilled syringes lines was significantly modified. Since January till July 2015, 49 batches were manufactured in that area without qualification after the change. During the inspection it was found that: 1) pressure differential between clean areas B and C grade were usually below 10 Pa (effective to < 0 Pa) and alarm (generated electronically, non-validated after the change of the system) has triggered at 0 Pa and after reversing the flow; 2.) laminar air flow system did not comply with requirements given in Annex 1; 3.) test of maximum permitted number of particles “in operation” does not perform properly; 4.) technical condition of clean areas and equipment show lack of proper and regular maintenance. In clean areas A/B grade contamination were found on the arm of the filling machine for prefilled syringes and difficult to clean equipment placed without proper SOP. In grade C e.g. crumbling insulation of pipes, peeling teflon on the ports of tanks and pumps, lack of labelling and mixed clean and dirty equipment, chipped glass accessories was found; 5.) the filtration process was not fully validated and during routine process a pressure difference to be used across the filter was not recorded; 6.) lack of confirmation of A grade in a lyophilizer working in a nitrogen atmosphere; 7.) design, installation and use of nitrogen system did not guarantee tightness and can cause contamination of the clean medium.
HUBEI HONGYUAN PHARMACEUTICAL CO., LTD. , China
This inspection was performed in the framework of the CEP dossier for the manufacture of Metronidazole R1-CEP 2007-309-Rev 01. The inspection identified in total 24 deficiencies to EU GMP. One of them was categorized as critical and related to the Company’s Quality Assurance System for production of Metronidazole. 10 deficiencies were categorized as major and were related to: QA, Documentation, Supplier Qualification, Data Integrity, Out-of-Specification handling, Quality Control, Computerised System validation, Change Control.
HUBEI HONGYUAN PHARMACEUTICAL CO., LTD. (Facility 428) , China
The Company’s facility at No. 428 Yishui North Road, Fengshan Town, Luotian County, Huanggang City, Hubei Province, China was subject to a spot check, because this site is mentioned as an intermediate manufacturing site in CEP 2001-450 Metronidazole. The Company clearly stated in their introduction that the site does not follow EU GMP. The following observations were made and together categorized as critical: a. The manufacturing site and it’s equipment was found in a devastated state. b. Huge layers of dust and product indicated that no cleaning was applied to either the facility or the equipment, leading to an extreme risk of cross-contamination. c. The extremely bad shape of the facility and the equipment showed that no maintenance was in place. d. Almost none of the products seen was labelled. e. No batch manufacturing documentation could be seen. Reference: EU GMP Part II was found not implemented at the facility.
SAS JARMAT « LABORATOIRE ADP », France
As a preliminary note, the starting materials repacked by the site were intended for pharmaceutical compounding activity in community pharmacies. The site did not distribute to the industry. Overall, 21 deficiencies were found, including 3 critical deficiencies and 5 major deficiencies: [Critical 1] Important risks of confusion in the repacking operations were identified. [Critical 2] Important risks of cross contamination in the repacking operations by substances of high pharmacological activity or toxicity were identified. [Critical 3] The active substances and excipients batches were not analysed as per the pharmacopoeial specifications. [Major 1] The release of active substances batches was deficient, notably in the absence of batch production records. [Major 2] Several risks of contamination in the sampling operations, notably cross contamination, were identified. [Major 3] The management of active substance suppliers was deficient, notably in the absence of written confirmation. [Major 4] Several risks of contamination in the repacking operations, notably cross contamination, were identified. [Major 5] The transmission of information to pharmacies was incomplete and confusing, notably regarding the analyses actually performed by the site. The inspection’s observations also apply to excipients, which are repacked and distributed under the same conditions as the active substances.
Svenska Bioforce AB, Sweden
During the inspection, 42 deficiencies were found. None of the deficiencies was critical but 17 were major. The 17 major deficiencies related to batch certification, Product Quality Review, change management system, deviation handling system, management responsibility, training, premises and equipment, documentation, line clearance, quality control, complaint handling, and cleaning validation. Re-inspection after implementation of CAPA is required in order to verify that the Pharmaceutical Quality System meets the requirements according to EU-GMP.
CARGILL FRANCE, France
Overall, 14 observations were made, including 1 critical deficiency and 4 major deficiencies: [Critical] The management of semi-finished batches and of the mixing operations was deficient and conformity of the final batches to specifications, notably Ph.Eur. specifications, could not be guaranted. [Major 1] The site had been manufacturing an active substance without ANSM authorisation. [Major 2] The change control related to the suppression of one filtration step in the active substance manufacturing process was deficient. [Major 3] The manufacturing of the active substance had not been made using master production instructions and no batch production records had been established. [Major 4] No review of batch production records of critical process steps had been done before release of the active substance for distribution. 7 observations are related to lack of traceability, risks of contamination induced by the absence of cleanliness in the production environment, very bad condition of the production equipment and insufficient equipment cleaning procedures. The inspection’s observations also apply to the manufacture of pharmaceutical excipients and starting materials that are intended to be used as ingredients in cosmetics and medical devices, which are manufactured under the same conditions as the active substance.
FARMA MEDITERRANIA, S.L., Spain
Critical deficiencies a) Lack of an effective pharmaceutical quality assurance system b) Release of batches of medicinal products produced without completing all of the manufacturing protocols, without being checked quality assurance unit and without the approval of the technical director. c) Use in quality control a non-qualified chromatographic equipment, with operating faults and with an unvalidated computerized management system. As a result, the integrity, reliability, up-to-dateness, originality and authenticity of the data that are obtained cannot be guaranteed. d) Transfer of some of the final analytical quality controls of medicinal products to a third party, without appropriately transferring the control methods and without the authorization of the relevant health authority e) Manufacture of medicinal products using procedures that have not been appropriately validated or have not been periodically revalidated. f) Acceptance of results of repeated analytical controls and sterility tests of finished medicinal products without having undertaken an in-depth investigation to determine the root cause of a previously result obtained which was out of specifications. g) Although a visual inspection of injectable medicinal products reveals a high number of critical quality defects (the presence of visible particles) non deviations are opened and is not investigated. c) Do not do any quality control on a statistical sample of units of injectable medicinal products that have passed the visual inspection. Major deficiencies a) Do not do the annual quality product review of medicinal products manufactured. b) Deviations in the manufacturing processes are not investigated suitably and in-depth. c) The simulation of the aseptic manufacturing process is not performed every six months and samples used in the simulation are not incubated at the right temperature. c) The air treatment system in manufacturing areas is not properly qualified, as it is only checked when it is “at rest” but not “in operation”. e) Medicinal products are manufactured without full compliance with conditions established in the marketing authorisation dossier and/or without carrying out all the established process controls. f) Manufacturing and quality control documents of each batch of medicinal products manufactured are not filed correctly. g) The facilities have been modified considerably without the authorization of the relevant health authority h) Test of growth promotion of culture media, which are used in the sterility testing, in the simulation of the aseptic manufacturing process or in the environmental control of critical manufacturing areas, is not carried out. h) Do not analyse all of the specification parameters for raw materials used in the manufacturing.
Chengdu Okay Pharmaceutical Co. Ltd., China
Overall, 21 deficiencies were observed during the inspection, including 5 critical and 10 major deficiencies. The critical deficiencies were observed in QC Dept. including calculation of impurities of Diosmin and there were no records of standard (used as a reference) for testing in-house standard. Also the data integrity was not guaranteed. In manufacturing Dept. presented measuring methods were inadequate to the results. The condition in clean area was not acceptable for final product. Critical deficiences: Testing of the final product: There was incorrectly way of calculation the impurities and Diosmin content. There were no records of prepared in-house HPLC standard. There was no confirmation of the conditions HPLC analysis. Computerized systems – documentation and control: There was found in HPLC system that the method was changed, without any savings of previous method. There were no logins and passwords to the HPLC system and no procedure for granting permission to access to the HPLC system. There was no register of persons authorized to access the HPLC system. On the same computer station there were two different HPLC software. Manufacturing documentation: Presented measuring methods of pH during the inspection time were inadequate to the results recorded in the batch report. Premises: Crude Diosmin drying was carried out in an area which did not provide the appriopriate coditions during the discharge from the dryer. Qualification of equipment: Some data of HVAC system qualification had been falsified. The major deficiencies were observed among others: in the warehouse, in the manufacturing documentation and in the production area.
Dongying Tiandong Pharmaceutical Co., Ltd., China
This serious Non-Compliance Report refers to a manufacturing site for Heparin. French Inspectors found 2 critical and 3 major deviations. Heparin manufacturing sites were involved in one of the largest counterfeit scandal ever. Therefore it is worrying that critical deviations in Heparin manufacturing have been found again. Read more in our GMP News Chinese Heparin Manufacturer again involved in Falsification and GMP Non-Compliance.
THERAVECTYS – VILLEJUIF, France
Here a manufacturing site for Investigational Medicinal Products (IMPs) is concerned. Overall 45 deficiencies, including 5 critical deficiencies and 17 major deficiencies have been detected. The following critical deviations in sterile production are listed in the agency report:
1) The implementation of exemption SOP for manufacturing operations which is not compliant to GMP principles, for example, Media Fill Test were performed with unqualified equipment.
2) The lack of sample area for incoming materials and their systematic use in quarantine status for manufacturing operations.
3) Appropriate measures in terms of monitoring locations, alert and action limits rationale, were not set for particle and microbiological monitoring in clean rooms grade A and B.
4) No protocol for clean rooms’ qualification was established and clean rooms classification didn’t fulfill ISO14644 requirements.
5) Some analytical methods and process were not validated for the clinical trial EudraCT : 2015-000845-21
It is about the term “complex manufacturing processes”, which is used in two scenarios associated with type II variations (found in the “detailed guidelines” p 40ff):
Replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product (Guideline change code B.II.b.1)
c) Site where any manufacturing operation(s) take place, except batch release, batch control, and secondary packaging, for biological/immunological medicinal products, or for pharmaceutical forms manufactured by complex manufacturing processes.
Change in the batch size (including batch size ranges) of the finished product (Guideline change code B.II.b.4)
d) The change relates to all other pharmaceutical forms manufactured by complex manufacturing processes .
The EMA now clarified this term as follows:
Guideline Change Code B.II.b.1: Complex manufacturing processes are given when the understanding of the relation between quality characteristics of the product and its in vivo efficacy is lacking. This is often the case in innovative medicines such as products of nanomedicine.
Guideline Change Code B.II.b.4: Complex manufacturing processes are those which contain one or more sub-steps, where a scale-up can lead to problems.
In both scenarios, the approving authority will decide on a case by case basis. If the applicant submits the variation as a Type IB, he must provide a valid justification that the production process is not “complex”. However, in doubt the authority may upgrade the variation to a Type II. Therefore, the EMA recommends that the applicant clarifies the situation with the authority before submitting the variation
In our News dated 18 February we reported on a question & answer (Q&A) paper which was published by EMA and FDA together at the end of 2014. This document answers questions on detailed requirements in connection with the documents concerning regulatory submissions. It also answers a question on the topic design of experiments (DOE).
The document answers the question “What level of detail should be considered for design of experiments (DOEs) in a regulatory submission?” as follows:
The level of detail should be commensurate with the significance of the outcome of the DOE to the selection of the product design, commercial manufacturing process and control strategy. According to the document a DOE to define operating ranges for an important unit operation would normally be considered of high significance. The information provided to the authority in such cases could include:
Type of experimental design and parameter ranges studied. As a supplement it is pointed out that justification for choice of design could be useful.
Tables summarizing inputs and outputs, including batch size.
Summary of parameters that were kept constant during the DOE.
Delineation of factors as scale dependent or independent, with justification (for example experimental results, scientific rationale, prior knowledge).
Description of main effects and interactions on response variables, including statistical significance of parameters (p-value).
Discussion of regression model validation parameters (such as output from ANOVA regression analysis, residual plots, etc.) if applicable.
Design of Experiments or short DoE is a process of designing experiments to understand and validate the relationship between a list of input factors and a desired output variable.
The article on DoE has already explained the importance and benefits of DoE, key terminologies like error, noise factors, correlation and interaction. This article will provide information that will be helpful to successfully plan a DoE.
The process of DoE has the following steps. We will look at details to be taken care at each step to successfully conduct a DoE.
The main purpose of Planning & Designing Experiments is to obtain maximum amount of information from a least or optimal number of experiments (runs) & trials.
Pre-Requisites of a DoE Planning
One must note the below points before designing & conducting Experiments.
Define the Problem:One must confirm whether a DoE is really needed for the problem taken. One should evaluate whether the required result or information can be obtained from any other source, or any set of calculations. There may be constraints in availability of raw materials & equipment. Some experiments may be very costly and time consuming. Therefore, DoE must be chosen when it is absolutely necessary and there are no other alternatives available.
Identify the objective of the study:There may be different objectives.
Exhaustive Study:One might need to know the complete list of variables/factors affecting the response variable. For this, afull factorial designis needed. No factors or levels should be omitted while conducting experiments.
Examine Specific factors:Sometimes, the business need will be to only validate the effect of a single or few parameters on the response variable. For this purpose, there is no need to conduct all the experiments.
Screening:The business need might be to identify only the vital few variables that have the maximum impact on response variable. One must study the Signal to Noise ratio, trivial factors that are not needed.
The number and set of experiments and trials will vary depending on the requirement. One must first ascertain the objective of the study to choose the appropriate design.
While planning and designing experiments the below items should be considered.
First use aDesign Matrixto identify all possible combinations of factors and levels. The Design matrix will help to identify all combinations and an experiment will be conducted for each row item.
The above table illustrates a Design matrix for a design that has two factors with two levels each. Each Factor-level combination has a unique experimental setup, which is called a Run. At a minimum, one experiment should be conducted per run.
Blocking of Variables/Factors:While organizing experiments, runs can be grouped in a specific order for the ease of conducting experiments. Runs with factors that are homogenous to each other are grouped as clusters and experiments may be conducted together or sequentially or combined, depending on the nature of variables. This process of grouping runs based on the behavior of factors is called as Blocking. One should look at opportunities for blocking to reduce time and effort. Blocking is also used to screen the effect of known sources of variation.
Randomization of Runs:It is known that there are interactions between factors which create a combined effect on the output variable. In addition to this, there may be some uncontrollable influences like change in equipment, raw material etc. To reduce the effect of these uncontrollable influences, the experiments should be conducted in no particular order but random, so that the effects are minimized.
Replication of Runs:Replication or repetition of experiments is done to dampen the effect of uncontrollable variation. Also it helps in acquiring precise estimation of response and to detect the S/N (Signal to Noise) ratio better. The number of trials depends on the precision of equipment. Therefore, it is necessary to conduct MSA before conducting DoE.
Order of Experiments:Experiments can be conducted either sequentially or in parallel. Sequential approach is required, when the outcome of one experiment is required to modify the set-up of further experiments. Otherwise, if there is enough equipment and manpower, Parallel runs will reduce the time spent on conducting experiments.
The above points will help in designing a perfect DoE plan that optimizes the number of runs and maximizes the data and information collected to meet the objective of the study.
More than three years ago, the EMA has published two draft documents for a template for the QP’s declaration concerning GMP compliance of the API used as starting material and verification of its supply chain called “The QP declaration template“:
1. The draft template for the Qualified Person’s declaration
2. the respective draft Q&A on the template for the Qualified Person’s declaration
The QP Declaration should be provided in support of an application for a new marketing authorisation, variation or renewal of a medicinal product(s) authorised in the Community, using EU or national procedures within the scope of the respective Directives.
The consultation for the template ended on 30 April 2011. In June 2014, the final version was published together with a template guidance. Now, three months after publication of the final document, the comments from 2011 have been published.
The answers to these comments also give some useful and interesting background information on EMA’s expectations when it comes to API supplier auditing and qualification.
The 93 page document shows that some comments provided by the various interest groups – like the European QP Association – have been taken into consideration, and a few suggestions for improvement have been implemented. When it comes to audit information, fewer details are requested now. Confirmation of the supply chain traceability has been deleted; the API “supply chain should be established, qualified and documented and addressed through GMP”.
The wording of the draft declaration ”I have evaluated each of the named contract acceptors… …. Audit(s) was/were conducted by properly qualified and trained staff….” has been changed to a more formal phrase, not implying the necessity for a personal check by the QP.
But EMA also declined many industry proposals for the QP Declaration:
Some stakeholders thought that most of information being requested in the template should be part of GMP audit or supplier qualification programme rather than to inclusion in a regulatory dossier submission. But the template is still part of the regulatory submission. And EMA still considers a maximum three year period for API audits as good practice. Exceptions to this standard might only be possible on a case by case basis, which cannot be generalised.
The wish that GMP certificates from a relevant Competent Authority can replace audits by the company will remain a wish. EMA refers to its Q&A document* where it is stated that audits should be performed by or on behalf of the Marketing Authorisation Holder or acceptable third party auditors. However “API manufacturing sites, which have been inspected by an EU Competent Authority and found GMP non-compliant, should not be used as sources of API”. Audits by accredited audit bodies who audit on behalf of the contract acceptor are also not accepted. Furthermore the API supplier needs to be assessed and deemed satisfactory before purchase of the material. Only in exceptional cases, e.g. atypical actives, where the QP Declaration is not based on an on-site audit, then other documentation (not the QP template) will need to be submitted according to the guidance document and considered on a case by case basis. It will be possible to share API audits and audit reports, if supported by appropriate contract arrangements.
The fear of the European QP Association and other stakeholders, that disclosing (internal) audit reports during inspections by the Competent Authorities might trigger a process of parallel audit reports (one for the official part to show during inspection and in parallel a second one used internally) was not acknowledged. So GMP inspectors might request these audit reports during regulatory GMP inspections.
The request for a sufficient transition period of 24 months for the implementation of the QP declaration was declined (“not considered necessary”).
EMA emphasises that the QP Declaration should cover the designated starting material, as shown in the summary of the route of synthesis given in the DMF. Some stakeholders thought it might be better to refer to an Active Substance Master File (ASMF) and limit the QP Declaration only to the API manufacturing site involved in the last quality relevant manufacturing step.
This helps the Agency to meet its objective of making safe and effective medicines available to patients in a timely manner, following evaluation using state-of-the-art methods.
The Agency also supports the development of new therapies and technologies by working with interested parties in the European Union (EU).
Activities at the Agency
In 2004, the Agency set up the European Medicines Agency/Committee for Medicinal Products for Human Use (CHMP) Think-Tank Group on Innovative Drug Development.
This group included Agency staff and members of the CHMP and its working parties. Its work focused on identifying scientific bottlenecks and emerging science in the development of medicines, both in industry research and development and in academia, and on generating recommendations for future activities at the Agency:
In 2008 the EMA and its Scientific Committees integrated the recommendations made by the Think Tank in its strategy for supporting innovative medicines developments. Key areas of action included the strengthening of the EU scientific network model, emphasis on communication during the lifecycle of medicinal products development and international activities. Overview of measures implemented in the period 2008-2010.
The European Medicines Agency (EMA) has published draft best-practice guidance for industry on parallel scientific advice with health technology assessment (HTA) agencies, aimed at facilitating early dialogue between regulators, HTA bodies and drug developers.
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