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GMP’s for Early Stage Development of new Drug substances and products

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GMP’s for Early Stage Development of New Drug substances and products


The question of how Good Manufacturing Practice (GMP) guidelines should be applied during early stages of development continues to be discussed across the industry and is now the subject of a new initiative by the International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium)—an association of pharmaceutical and biotechnology companies aiming to advance innovation and quality in the development of pharmaceuticals. They have assembled a multidisciplinary team (GMPs in Early Development Working Group) to explore and define common industry approaches and to come up with suggestions for a harmonized approach. Their initial thoughts and conclusions are summarized in Pharm. Technol. 2012, 36 (6), 5458.
Image result for International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium)
From an industry perspective, it is common to consider the “early” phase of development as covering phases 1 and 2a clinical studies. During this phase, there is a high rate of product attrition and a high probability for intentionally introducing change into synthetic processes, dosage forms, analytical methods, and specifications. The quality system implemented during this early phase should take into account that these changes and adjustments are intrinsic to the work being performed prior to the determination of the final process and validation of the analytical methods during later stages of development.
Image result for “early” phase of development as covering phases 1 and 2a clinical studies
FDA guidance is already available on GMP requirements for phase 1 materials. (See Org. Process. Res. Dev. 2008, 12, 817.) Because many aspects of phase 2a clinical studies are similar in their scope and expectations, the working group feels there is an opportunity to extend this guidance across all early phase studies. Because products and processes are less well understood in the early phases of development, activities should focus on accumulating the appropriate knowledge to adequately ensure patient safety. Focusing on this area should ensure that beneficial therapies reach the clinic in an optimum time scale with minimal safety concerns.
Image result for “early” phase of development as covering phases 1 and 2a clinical studies
A follow-up article ( Pharm. Technol. 2012, 36 (7), 76−84) describes the working group’s approach to the subject of Analytical Method Validation. Their assessment has uncovered the need to differentiate the terms “validation” and “qualification”. Method qualification is based on the type, intended purpose, and scientific understanding of the type of method in use. Although not used for GMP release of clinical materials, qualified methods are reliable experimental methods that may be used for characterization work such as reference standards and the scientific prediction of shelf life. For example, in early development it would be sufficient for methods used for in-process testing to be qualified, whereas those methods used for release testing and for stability determination would be more fully validated.
In early development, a major purpose of analytical methods is to determine the potency of APIs and drug products to ensure that the correct dose is delivered in the clinic. Methods should also indicate stability, identify impurities and degradants, and allow characterization of key attributes. In the later stages, when processes are locked and need to be transferred to worldwide manufacturing facilities, methods need to be cost-effective, operationally viable, and suitably robust such that the methods will perform consistently. irrespective of where they are executed.
The authors advocate that the same amount of rigorous and extensive method-validation experiments, as described in ICH Q2, “Analytical Validation”, is not needed for methods used to support early stage drug development. For example, parameters involving interlaboratory studies (i.e., intermediate precision, reproducibility, and robustness) are not typically performed during early phase development, being replaced by appropriate method-transfer assessments and verified by system suitability requirements. Because of changes in synthetic routes and formulations, the impurities and degradation products formed may change during development.
Accordingly, related substances are often determined using area percentage by assuming that the relative response factors are similar to that of the API. As a result, extensive studies to demonstrate mass balance are typically not conducted during early development.
Detailed recommendations are provided for each aspect of method validation (specificity, accuracy, precision, limit of detection, limit of quantitation, linearity, range, robustness) according to the nature of the test (identification, assay, impurity, physical tests) for both early- and late phase development. These recommendations are also neatly summarized in a matrix form.
Above text drew attention to a series of articles from the IQ Consortium (International Consortium on Innovation and Quality in Pharmaceutical Development) on appropriate good manufacturing practices (GMP) for the early development phases of new drug substances and products. The fifth article in this series(Coutant, M.; Ge, Z.; McElvain, J. S.; Miller, S. A.; O’Connor, D.; Swanek, F.; Szulc, M.; Trone, M. D.; Wong-Moon, K.; Yazdanian, M.; Yehl, P.; Zhang, S.Early Development GMPs for Small-Molecule Specifications: An Industry Perspective (Part V) Pharm. Technol. 2012, 36 ( 10) 8694) focuses on the setting of specifications during these early phases (I and IIa).
Due to the high attrition rate in early development, the focus should be on consistent specifications that ensure patient safety, supported by preclinical and early clinical safety studies. On the basis of the cumulative industry experience of the IQ working group members, the authors of this paper propose standardized early phase specification tests and acceptance criteria for both drug substance and drug product. In addition to release and stability tests, consideration is given to internal tests and acceptance criteria that are not normally part of formal specifications, but which may be performed to collect information for product and process understanding or to provide greater control.
Image result for preclinical animal studies
The drug substance used in preclinical animal studies (tox batch) is fundamental in defining the specifications for an early phase clinical drug substance (DS). Here, internal targets rather than formal specifications are routinely used while gathering knowledge about impurities and processing capabilities. At this stage the emphasis should be on ensuring the correct DS is administered, determining the correct potency value, and quantitating impurities for toxicology purposes. For DS intended for clinical studies, additional testing and controls may be required; the testing may be similar to that for the tox batch, but now with established acceptance criteria. For these stages the authors propose a standardized set of DS specifications, as follows.
Description range of colour
identification conforms to a reference spectrum
counterion report results
assay 97–103% on a dry basis
impurities NMT 3.0% total, NMT 1.0% each
unidentified NMT 0.3%
unqualified NMT 0.15%
mutagenic follow EMA guidelines (pending ICH M7 guidance)
inorganic follow EMA guidelines (pending ICH Q3D guidance)
residual solvents use ICH Q3C limits or other justified limits for solvents used in final synthetic step
water content report results
solid form report results
particle size report results
residue on ignition NMT 1.0%
These may be altered in line with any specific knowledge of the compound in question. For example, if the DS is a hydrate or is known to be hygroscopic or sensitive to water, a specified water content may be appropriate. Of particular note is the use of impurity thresholds which are 3 times higher than those defined in ICH Q3 guidelines. Q3 was never intended to apply to clinical drugs, and higher thresholds can be justified by the limited exposure that patients experience during these early stages. Mutagenic impurities are the exception here, since in this area the existing official guidance does cover clinical drugs.
The fourth article in the series(Acken, B.; Alasandro, M.; Colgan, S.; Curry, P.; Diana, F.; Li, Q. C.; Li, Z. J.; Mazzeo, T.; Rignall, A.; Tan, Z. J.; Timpano, R.Early Development GMPs for Stability (Part IV) Pharm. Technol. 2012, 36 ( 9) 6470) considers appropriate approaches to stability testing during early clinical phases. Appropriate stability data at suitable storage conditions are required to support filing the clinical trial application (CTA/IND/IMPD) and use of the clinical material through the end of the clinical study. Several factors from business, regulatory, and scientific perspectives need to be taken into account when designing early stability studies, such as the risk tolerance of the sponsoring organization, the inherent stability of the drug substance and prior product, process and stability knowledge, the regulatory environment in the countries where the clinical trial will be conducted, and the projected future use of the product.
Often non-GMP DS batches are manufactured first and placed on stability to support a variety of product development activities.In many cases these batches will be representative of subsequent GMP batches from a stability perspective and can be used to establish an initial retest period for the DS and support a clinical submission. In early development, it is common for the manufacturing process to be improved; therefore, as the DS process evolves, an evaluation is needed to determine whether the initial batch placed on stability is still representative of the improved process. The authors advocate a science- and risk-based approach for deciding whether stability studies on new process batches are warranted.
The first step is to determine which DS attributes have an effect on stability. This step can be completed through paper-based risk assessments, prior knowledge, or through a head-to-head short-term stability challenge. If the revised process impacts one or more of these stability-related quality attributes, the new batch should be placed on stability—otherwise not. Typical changes encountered at this stage include changes in synthetic pathway, batch scale, manufacturing equipment or site, reagents, source materials, solvents used, and crystallization steps.
Image result for DS stability
In most cases, these changes will not result in changes in DS stability. Changes to the impurity profile are unlikely to affect stability, since most organically related impurities will be inert. On the other hand, catalytic metals, acidic or basic inorganic impurities, or significant amounts of residual water or solvents may affect stability; thus, changes to these attributes would typically require the new batch to be placed in the stability program. Similarly, any changes to polymorphic form, particle size, or counterion would warrant extra testing. Packaging changes of the bulk material to a less protective package may require stability data to support the change.
Three approaches to stability data collection are commonly used. One is that an early, representative DS batch is placed under real-time and accelerated conditions (e.g., 25 °C/60% RH and 40 °C/75% RH), and stability results for a few time points (e.g., 1–6 months) are generated to support an initial retest period (e.g., 12 months or more). A second approach is to use high stress conditions such as a high temperature and high humidity with a short time. A third approach is the use of stress studies at several conditions coupled with modelling. The retest period derived from these types of accelerated or stress studies can be later verified by placing the first clinical batch into real-time stability studies under ICH accelerated and long-term conditions. Future extensions of the retest/use period can be based on real-time data.

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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Already 13 EMA GMP Non-compliance Reports in 2016 published

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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. Please get the details about the GMP non-compliance findings at 11 manufacturers in Europe and abroad.

http://www.gmp-compliance.org/enews_05224_Already-13-EMA-GMP-Non-compliance-Reports-in-2016-published_15159,S-QSB_n.html

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

All Non-Compliance Reports with the detailed address of the facilities and the product concerned can be found in the EudraGMDP Database.

///////////// 13 EMA,  GMP Non-compliance Reports, 2016 published, EudraGMDP,  central database

ECA publishes revised version of Good Practice Guide on Process Validation

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After the FDA moved towards a life cycle approach with its Process Validation Guidance in 2011, the EU GMP Guide now followed with the revision of Annex 15, also moving to modern process aspects (e.g. life cycle approach). But how can the industry implement the new process validation requirements? The ECA’s Good Practice Guide on Validation does provide answers.

Since the publication of FDA´s Process Validation Guidance in 2011, validation has become a life cycle approach with focus on process knowledge and process understanding based on scientific sound principles. In addition, with the revision of Annex 15 of the EU GMP Guide, the EU has also been moving to modern process aspects (e.g. life cycle approach).

The question is how to implement these new requirements – in the USA and  in Europe?

To answer this question, an ECA Working Group has revised the Version 1 of ECA´s Good Practice Guide on Validation. With the revision the group wants to provide support to both regulators and industry. On one hand, the guide contains the main elements of the new approach (“what to do”). On the other hand, it also serves as a supporting guide for the implementation (“how to do”).

The revised version comprises 174 pages divided in 5 chapters and 5 annexes (with detailed analyses of the regulatory guidances).

The topics covered are e.g.:

  • risk based qualification and validation
  • legacy products
  • statistics
  • case study about process validation
  • case study about continued/ongoing process verification in biopharmaceutical manufacturing

The ECA Good Practice Guide on Validation will be officially launched at ECA´s Annex 15 Conference on 25/26 November 2015 in Berlin. All participants will receive a free copy of the document.

http://www.gmp-compliance.org/enews_05089_ECA-publishes-revised-version-of-Good-Practice-Guide-on-Process-Validation_9379,15093,15290,15163,Z-VM_n.html

 

ECA´s Annex 15 Conference on 25/26 November 2015 in Berlin. All participants will receive a free copy of the document.

Course No 9379

Annex 15 Conference

25-26 November 2015, Berlin, Germany

Background

Since 2001 the Annex 15 has been state of the art for Validation Master Plan, Qualification, Validation, Cleaning Validation and Change Control within the EU. In the meantime ICH
Q 8-11 has been published. The FDA has implemented most of these ICH guidelines and introduced a Validation Process Life Cycle in its Process Validation Guidance from 2011. The EMA has published a revision of its Note for Guidance on Process Validation to implement this new aspects too. This is also the reason why the Annex 15 has to be revised. The first thoughts have been provided in a concept paper. In February 2014 was a draft published and now the final version of the revision is available.

Programme

ECA Annex 15 Survey
Industry view on Annex 15

Overview of the new Annex 15 revision view of an EU GMP Inspector
History of validation guidelines in the EU
The Annex 15 revision
The EMA Process Validation revision
What´s really new?

Organisation and Planning for Qualification and Validation
Integration of outsourced data in a validation
What is an “appropriate validation oversight” ?
New requirements in the Validation Master Plan
Requirements regarding the qualification of suppliers
Requirements regarding Risk Management

Validation Documentation
Good Documentation Practice – what does that mean for validation?
How to support knowledge management
Content of validation protocols and reports
Conditional approvals – a challenge

Qualification – Annex 15 revision vs FDA Process Validation Guidance
The new first step(s) URS/FDS
How to use FAT and SAT?
Combinations of qualification stages IOQ/OPQ
Interface PQ/Process Validation
Is the requirement to qualify utilities really new?
How to handle the qualification of established equipment (in-use) in the future?
What´s about alternatives (ASTM E 2500)?
Are there differences to the FDA Process Validation Guidance?

Process Validation in the new Annex 15 revision – in the light of modern
life cycle thinking
The Process Validation Life Cycle
Modern vs. traditional approach
What is a hybrid approach?
How is bracketing possible?
Are the three magic runs still applicable?
Clarification of the terms continuous process verification, continued process verification, ongoing process verification
Is the Annex 15 revision in line with the FDA Process Validation Guidance?

Cleaning validation in the new Annex 15 – how to implement the PDE concept?
Grouping of equipment – a new possibility?
How to validate manual cleaning operations`
The new acceptance criteria: PDE – how to implement?
Choice of worst case products taking account of toxicity PDE values and solubility
How to determine the cleaning validation batches?
Cleaning verification – what´s that?

Transport verification – solutions for future challenges
Requirements of Annex 15
Regulatory expectations
Qualification, Verification, Validation
Lean Verification Approach
Actual status, future challenges

Packaging Validation – from fill to finish
Requirements of Annex 15
Qualification of packaging lines
The validation of primary vs secondary packaging processes

 

 

BERLIN, GERMANY

Map of berlin

 

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Actual Interpretation of the GMP Requirements for Active Pharmaceutical Ingredients: APIC revises the “How to do” Document on ICH Q7

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Actual Interpretation of the GMP Requirements for Active Pharmaceutical Ingredients: APIC revises the “How to do” Document on ICH Q7

The APIC has thoroughly revised the “How to do” document that explains the guideline ICH Q7. Here you can see how the new document interprets the requirements concerning a GMP compliant manufacture of active pharmaceutical ingredients against the background of the current developments.

 

Shortly after the entry into force of the Good Manufacturing Guide for Active Pharmaceutical Ingredients ICH Q7 in the year 2000 the Active Pharmaceutical Ingredients Committee APIC wrote the “How to do” document which clarifies the requirements of the guideline on the basis of experience gained from operational practice. The present document aims at providing practical advice for the implementation and maintenance of GMP standards during the production of active pharmaceutical ingredients concerning those provisions of ICH Q7 that require further interpretation. The “How to do” document is a “living” document as it is revised in irregular intervals in order to keep pace with the constantly changing state of scientific and technical knowledge.

The recently revised version of the document was published as “Version 8” on the APIC publications website in August 2015. As compared to the last revision (August 2012) the chapters 10 “Storage and Distribution”, 11 “Laboratory Controls”, 12 “Validation” and 15 “Complaints and Recalls” were revised. The following is a selection of the most important changes:

Chapter 10 Storage and Distribution

  • This chapter points out the importance of controlling the temperature distribution in warehouses taking into account seasonal temperature changes. The document indicates sets of rules that describe concretely how to perform a temperature mapping (section 10.10.).
  • It stresses the necessity of physical separation between released and returned material, preferably by storing them in different rooms. Storage conditions for intermediates are based on development data and knowledge (section 10.11).
  • The document points out that logistics companies should be qualified (quality agreement). The shipping conditions records should be reviewed. If deviations occurred an investigation should be initiated and appropriate measures be carried out and documented (section 10.21).

Chapter 11 Laboratory Controls

  • This chapter expressly points out that analytical methods have to be validated and that the integrity of analytical data has to be ensured by means of controls (section 11.11).
  • Rounding rules and the process used for averaging should be described in a SOP (section 11.11.).
  • In chapter 11.13 ICH M7 and ICH Q3D have been added to the list of ICH guidelines. Furthermore, it is pointed out that the design of experiments approach can also be used within the framework of design space when defining specifications.
  • Chapter 11.15 contains detailed guidance on the FDA requirements for active pharmaceutical ingredients that are exported to the USA and sold there, especially on the handling of OOS results.

Chapter 12 Validation

  • Chapter 12.11 explains more in detail the handling of critical parameters and quality attributes referring to the actual ICH guidelines ICH Q8 and Q11 as well as to FDA and EMA guidelines.
  • It indicates that the 3 consecutive validation batches should be considered as an orientation. The actual number of validation batches has to be pre-defined and to be justified (section 12.50).
  • The process validation report has to contain all critical quality attributes compared to the reference batches. These attributes should be comparable to or better than the reference batches. The rationale for selecting the reference batches must be justified (section 12.52).

Chapter 15 Complaints and Recalls

  • This chapter refers to the necessity to include other batches potentially connected with the batch affected by the complaint or recall in the complaint investigation and to define a period to close complaint investigations (section 15.10).
  • It points out that a recall cannot be carried out by the API manufacturer himself. This is the responsibility of the finished dosage form manufacturer. The notification of the authorities (such as public health departments) can also only be carried out in close cooperation with the finished dosage form manufacturer (section 15.10).

As a whole the revised “How to do” document is a valuable aid for the implementation of the Good Manufacturing Practice in the production of active pharmaceutical ingredients. Due to the thorough revision of many sections it offers an up-to-date practice-oriented assistance every API manufacturing site can profit from

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EU: New GMP Implementing Act published

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The EU Commission has published a new public consultation on an Implementing Act on GMP principles and guidelines for medicinal products for human use.

The EU Commission has published a new public consultation on an Implementing Act on Principles and guidelines on good manufacturing practices for medicinal products for human use.

http://www.gmp-compliance.org/enews_05017_EU-New-GMP-Implementing-Act-published_9304,9232,10335,Z-QAMPP_n.html

The reason is that once Regulation (EU) No 536/2014 on clinical trials becomes applicable, manufacture and import of Investigational Medicinal Products (IMPs) for the use in clinical trials carried out under that Regulation cannot follow GMP for IMPs set out in Directive 2003/94/EC. They then have to be manufactured or imported under regulations laid down by the Delegated Act or other specified regulation. It is therefore necessary that Directive 2003/94/EC is revised by a new Implementing Directive on principles and guidelines of good manufacturing practice for medicinal products for human use (without IMPs).

The EU Commission states that because “good manufacturing practice for medicinal products for human use already exists and is generally well-functioning, there is no need to reinvent the wheel”. So the GMP related consultation documents carry over elements set out in Directive 2003/94/EC relating to medicinal products for human use.  GMPs for advanced therapy medicinal products will be introduced with a new provision.

How to document a Product Transfer? Example templates!

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All participants of the GMP training course “GMP-compliant Product Transfer” will receive a special version of the Guideline Manager CD including documents and templates useable for site change projects. Read more.

According to the European GMP-Rules, written procedures for tranfser activities and their documentation are required. For example, a Transfer SOP, a transfer plan and a report are now mandatory and will be checked during inspections.

As a participant of the GMP education course “GMP-compliant Product Transfer” in Prague, from 20-22 October 2015 you will receive a special version of the Guideline Manager CD with a special section concerning product transfers. This section contains, amongst others, a Transfer SOP and a template for a Transfer Plan. Both documents are in Word format and can immediately be used after adoption to your own situation.

Regulatory Guidance Documents like the WHO guideline on transfer of technology in pharmaceutical manufacturing and the EU/US Variation Guidelines, are also part of the Guideline Manager CD. Due to copyright reasons, this CD is not available for purchase and can only be handed out to participants of the transfer course.

http://www.gmp-compliance.org/eca_mitt_04875_9340,Z-PEM_n.html

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GMP IN AN API PILOT PLANT

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GMP……API PILOT PLANT

PRESENTATION

 

Pilot plant and scale-up techniques are both integral and critical to drug discovery and development process for new medicinal products. A major decision focuses on that point where the idea or process is advanced from a research oriented program targeted towards commercialization.

The speed of drug discovery has been accelerating at an exponential rate. The past two decades particular have witnessed amazing inventions and innovations in pharmaceutical research, resulting in the ability to produce new drugs faster than even before.

The new drug applications (NDAs) and abbreviated new drug applications (ANDA) are all-time high. The preparation of several clinical batches in the pilot plant provides its personnel with the opportunity to perfect and validate the process. Also different types of laboratories have been motivated to adopt new processes and technologies in an effort to stay at the forefront scientific innovation.

MY PRESENTATION

 

 

Pharmaceutical pilot plants that can quickly numerous short-run production lines of multiple batches are essential for ensuring success in the clinical testing and bougainvilleas study phases. Drug formulation research time targets are met by having a well-designed facility with the appropriate equipment mix, to quickly move from the laboratory to the pilot plant scale 1. In pilot plant, a formula is transformed into a viable, robust product by the development of a reliable and practical method of manufacture that effects the orderly transition from laboratory to routine processing in a full scale production facility where as the scale up involves the designing of prototype using the data obtained from the pilot plant model.

Pilot plant studies must includes a close examination of formula to determine its ability to withstand batch-scale and process modifications; it must includes a review of range of relevant processing equipment also availability of raw materials meeting the specification of product and during the scale up efforts in the pilot plant production and process control are evaluated, validated and finalized.

pilot pic 12

In addition, appropriate records and reports issued to support Good Manufacturing Practices and to provide historical development of the production formulation, process, equipment train, and specifications

A manufacturer’s decision to scale up / scale down a process is ultimately rooted in the economics of the production process, i.e., in the cost of material, personnel, and equipment associated with the process and its control.

When developing technologies, there are a number of steps required between the initial concept and completion of the final production plant. These steps include the development of the commercial process, optimization of the process, scale-up from the bench to a pilot plant, and from the pilot plant to the full scale process. While the ultimate goal is to go directly from process optimization to full scale plant, the pilot plant is generally a necessary step.

Reasons for this critical step include: understanding the potential waste streams, examination of macro-processes, process interactions, process variations, process controls, development of standard operating procedures, etc. The information developed at the pilot plant scale allows for a better understanding of the overall process including side processes. Therefore, this step helps to build the information base so that the technology can be permitted and safely implemented.

Should be versatile pilot plant that is entirely GMP and facilitates the development of API’s in scalable, safe and environmentally friendly ways.

pilot pic 6

The combination of facilities, experience and flexibility enable an integral Contract Manufacturing service ranging from laboratory to industrial scale; it should manufacture under regulation small amounts of high added value active substances or key intermediate products.

pilot pic 4

 

pilot pic 5

Product quality: Operations that depend on people for executing manual recipes are subject to human variability. How precisely are the operators following the recipe? Processes that are sensitive to variations in processing will result in quality variation. Full recipe automation that controls most of the critical processing operations provides very accurate, repeatable material processing. This leads to very highly consistent product quality.

pilot pic 11

 Improved production: Many biotech processes have extremely long cycle times (some up to 6 months), and are very sensitive to processing conditions. It is not uncommon for batches to be lost for unexplained reasons after completing a large portion of the batch cycle time. The longer the batch cycle time and the more sensitive production is to processing conditions, the more batch automation is justified. Imagine losing a batch of very valuable product because the recipe was not precisely followed!

 Process optimization: Increasing the product yield can be done by making small changes in processing conditions to improve the chemical conversions or biological growth conditions. Manual control offers a limited ability to finely implement small changes to processing conditions due to the inherent lack of precision in human control. Conversely, computers are very good at controlling conditions precisely. In addition, advanced control capabilities such as model predictive control can greatly improve process optimization. This results in higher product yield and lower production cost. This consideration is highly relevant to pilot plant facilities where part of the goal is to learn how to make the product.

 Recordkeeping: A multi-unit recipe control system is capable of collecting detailed records as to how a batch was made and relates all data to a single batch ID. Data of this nature can be very valuable for QA reporting, QA deviation investigations, and process analysis.

 Safety: Operators spend less time exposed to chemicals when the process is fully automated as compared to manual control. Less exposure to the process generally results in a safer process.

A good batch historian should be able to collect records for a production run to include the following information:  Product and recipe identification

 User defined report parameters

 Formulation data and relevant changes

 Procedural element state changes (Operations, unit procedures, procedures)

 Phase state changes

 Operator changes

 Operator prompts and responses

 Operator comments

 Equipment acquisitions and releases

 Equipment relationships

 Campaign creation data (recipe, formula values, equipment, etc.)

 Campaign modifications

 Campaign execution activity

 Controller I/O subsystem events from the Continuous Historian

 Process alarms

 Process events

 Device state changes.

 

Raw materials

Buildings and facilities. GMPs under the 21 Code of Federal Regulations (CFR) Part 211.42 state that buildings or areas used in the receiving, storage, and handling of raw materials should be of suitable size, construction and location to allow for the proper cleaning, maintenance, and operation (7). The common theme for this section of CFR Parts 210 and 211 is the prevention of errors and contamination. In principle, the requirements for buildings and facilities used in early phase manufacturing are not significantly different than those for later phases or even commercial production. However, there are some areas that are unique to early clinical trial manufacturing.

Control of materials. The CFR regulations under Part 211.80 provide good direction with respect to lot identification, inventory, receipt, storage, and destruction of materials (7). The clear intent is to ensure patient safety by establishing controls that prevent errors or cross-contamination and ensure traceability of components from receipt through clinical use. In general, the requirements for the control of materials are identical across all phases of development, so it is important to consider these requirements when designing a GMP facility within a laboratory setting.

Combination Glass/Glass-lined reactors

For example, all materials must be assigned a unique lot number and have proper labeling. An inventory system must provide for tracking each lot of each component with a record for each use. Upon receipt, each lot should be visually examined for appropriate labeling and for evidence of tampering or contamination. Materials should be placed into quarantine or in the approved area or reject area with proper labeling to identify the material and prevent mix-ups with other materials in the storage area. Provision should be made for materials with special storage requirements (e.g., refrigeration, high security). The storage labeling should match the actual conditions that the material is being stored and should include expiry/retest dates for approved materials. Although such labeling is inconvenient for new materials where the expiration or retest date may change as more information is known, this enables personnel to be able to determine quickly whether a particular lot of a material is nearing or exceeding the expiration or retest date. General expiry/retest dates for common materials should be based on manufacturer’s recommendation or the literature.

Finally, there are clear regulatory and environmental requirements for the destruction of expired or rejected materials. It is important to observe regional and international requirements regarding the use of animal sourced materials (12). It is recommended to use materials that are not animal sourced and that there be available certification by the raw material manufacturers that they contain no animal sourced materials. If animal sourced raw materials must be used, then certifications by the raw material manufacturers that they either originate from certified and approved (by regulatory bodies) sources for use in human pharmaceuticals, or that the material has been tested to the level required for acceptance by regulatory agencies (following US, EU, or Japanese guidelines, as applicable) is required.

Direct advantages for customers

  • Shorter implementation time for product by determination of the product suitability as well as the necessary process cycle
  • Optimized adjustment of the processing times in the production lines (trains) by relatively precise estimation of the drying times
  • Definition of effective cleaning processes (CIP/WIP and SIP)
  • Definition of the selection criteria based on the weighting of the customer, e.g.: drying time, quality (form of crystal, activity, etc.), cleanout, ability of CIP, price

 

An overview of further trials and test functions, that can be realized in the new pilot plant facility:

  • Product tests for determination of suitability
  • Scale-up tests as basis for the extrapolation on production batches regarding drying time, filling degree, crystalline transformation and grain spectrum
  • Optimization of the process cycle
  • Optimization of the machine
  • Data acquisition and analysis

SEE THIS SECTION IN ACTION…………..KEEP WATCHING

Case study 1

Designed and equipped for the manufacturing of solid oral dosage form
Hammann

PlantaFabri

Designed and equipped for the manufacturing of solid oral dosage forms, specialized in high-activity substances (cytostatic, cytotoxic, hormonal, hormone inhibitors). It has ancillary areas for the proper management of materials intended for clinical trials of new drugs.

Equipment:

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CASE STUDY 2

OPERATION OF PILOT PLANT FOR CLINICAL LOTS OF BIOPHARMACEUTICALS

http://www.peq.coppe.ufrj.br/biotec/presentations/Papamichael_RioDeJaneiro2009_secure.pdf

 

pilot pic

 

pilot pic 2

 

pilot pic 3

 

 

pilot pic 7

CASE STUDY 3

 

Good Manufacturing Practices in Active Pharmaceutical Ingredients Development

http://apic.cefic.org/pub/5gmpdev9911.pdf

Example below

3. Introduction Principles basic to the formulation of this guideline are: ·

Development should ensure that all products meet the requirements for quality and purity which they purport or are represented to possess and that the safety of any subject in clinical trials will be guaranteed. ·

During Development all information directly leading to statements on quality of critical intermediates and APIs must be retrievable and/or reconstructable. ·

The system for managing quality should encompass the organisational structure, procedures, processes and resources, as well as activities necessary to ensure confidence that the API will meet its intended specifications for quality and purity. All quality related activities should be defined and documented. Any GMP decision during Development must be based on the principles above.

During the development of an API the required level of GMP control increases. Using these guidelines, the appropriate standard may be implemented according to the intended use of the API. Firms should apply proper judgement, to discern which aspects need to be addressed during different development stages (non-clinical, clinical, scale-up from laboratory to pilot plant to manufacturing site).

Suppliers of APIs and/or critical intermediates to pharmaceutical firms should be notified on the intended use of the materials, in order to apply appropriate GMPs. The matrix (section 8) should be used in conjunction with text in section 7, as is only intended as an initial guide. READ MORE AT…. http://apic.cefic.org/pub/5gmpdev9911.pdf

 

CASE STUDY 4

http://www.steroglass.it/doc_area_download/ita/process/20LT_PILOT_PLANT.pdf

pilot pic 8

 

 

CASE STUDY 5

 

Health Canada

http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/question/gmp-bpf-eng.php

The Good Manufacturing Practices questions and answers (GMP Q&A) presented below have been updated following the issuance of the “Good Manufacturing Practices Guidelines, 2009 Edition Version 2 (GUI-0001)“.

This Q&A list will be updated on a regular basis.

Premises – C.02.004

Equipment – C.02.005

Personnel – C.02.006

Sanitation – C.02.007 & C.02.008

Raw Material Testing – C.02.009 & C.02.010

Manufacturing Control – C.02.011 & C.02.012

Quality Control Department – C.02.013, C.02.014 & C.02.015

Packaging Material Testing – C.02.016 & C.02.017

Finished Product Testing – C.02.018 & C.02.019

Records – C.02.020, C.02.021, C.02.022, C.02.023 & C.02.024

Samples – C.02.025 & C.02.026

Stability – C.02.027 & C.02.028

Sterile Products – C.02.029

 

 

 

CASE STUDY 6

CASE STUDY 7

 

http://www.niper.gov.in/tdc_2013.pdf

 

 

 

CASE STUDY 8

Multi-kilo scale-up under GMP conditions

Examples of flow processes being used to produce exceptionally large amounts of material are becoming increasingly common as industrial researchers become more knowledgeable about the benefits of continuous reactions. The above examples from academic groups serve to illustrate that reactions optimized in small reactors processing tens to hundreds of mg hour−1 of material can be scaled up to several grams per hour. Projects in process chemistry are often time-sensitive, however, and production of multiple kg of material may be needed in a short amount of time. An example of how the efficient scaling of a flow reaction can save time and reduce waste is provided by a group of researchers at Eli Lilly in their kg synthesis of a key drug intermediate under GMP conditions . In batch, ketoamide 13 was condensed with NH4OAc and cyclized to form imidazole 14 at 100 °C in butanol on a 1 gram scale. However, side product formation became a significant problem on multiple runs at a 250 g scale. It was proposed that this was due to slow heat up times of the reactor with increasing scale, as lower temperatures seemed to favour increased degradation over productivecyclization. Upon switching to a 4.51 mL flow reactor, another optimization was carried out which identified methanol as a superior solvent that had been neglected in batch screening due to its low boiling point at atmospheric pressure. Scale-up to a 7.14 L reactor proceeded smoothly without the need for reoptimization, and running on this scale with a residence time of 90 minutes for a six-day continuous run provided 29.2 kg of product after recrystallization (approximately 207 g hour−1). The adoption of a flow protocol by a group of industrial researchers in a scale-up with time constraints demonstrates both the effectiveness and maturity of flow chemistry. While the given reaction was used to produce kilograms of material for a deadline, continuous operation without further optimization could produce over 1 metric tonne of product per year in a reactor that fits into a GC oven.

Kilogram-scale synthesis of an imidazole API precursor.
Scheme 20 Kilogram-scale synthesis of an imidazole API precursor.

 

 

 

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Definitions

Plant: A plant is a place where an industrial or manufacturing process takes place. It may also be expressed as a place where the 5 M’s that are; man, materials, money, method and materials are brought together for the manufacture of products.

Pilot Plant: A part of a manufacturing industry where a laboratory scale formula is transformed into a viable product by development of reliable practical procedures of manufacturing.

Scale-Up: This is the art of designing a prototype based on the information or data obtained from a pilot plant model.

cGMP: current Good Manufacturing Processes refer to an established system of ensuring that products are consistently produced and controlled according to quality standards. It is designed to minimize risk involved in any industrial design. GMP covers all aspects of production from the starting materials, premises and equipment to the training and personal hygiene of staff within industries. Detailed, written procedures are essential for each process that could affect the quality of the finished product. There must be a system to provide documented proof that correct procedures are consistently followed at each step in the manufacturing process every time a product is made.

SCALING UP FROM PILOT PLANTS

When scaling up, it is of utmost importance to consider all aspects of risk and futuristic expansion. The pilot plant is usually a costly apparatus and therefore the decision of building it is always a hard one. The function of a pilot plant is not just to prove that the laboratory experiments work, but;

  1. To test technologies that are about to be implemented on industrial plants before establishment
  2. To evaluate performance specifications before the actual installation of industrial plant.
  3. Evaluation of reliability of mathematical models within real environment.
  4. Economic considerations for production involving process optimization and automated control systems.

GMP GENERAL PRACTISES

Facilities and Equipment Systems

  • Ø Cleaning and maintenance
  • Ø Facility layout and air handling systems for prevention of cross-contamination (e.g. Penicillin, beta-lactams, steroids, hormones, cytotoxic, etc.)
  • Ø Specifically designed areas for the manufacturing operations performed by the firm to prevent contamination or mix-ups.

Facilities

  • Ø General air handling systems
  • Ø Control system for implementing changes in the building
  • Ø Lighting, potable water, washing and toilet facilities, sewage and refuse disposal
  • Ø Sanitation of the building, use of rodenticides, fungicides, insecticides, cleaning and sanitizing agents.

GMP FOR PLANT DESIGN

The application of GMP to plant design is primary to the establishment of such plants. Regulatory boards have precedence over these operations helping to establish a proper and functional system in plant design.

Design Review

l Conceptual drawings;

From plant design drawings which are inspected and approved by cGMP regulatory bodies (such as Department of Petroleum Resources in Nigeria), approvals are issued depending on adherence to specifications such as muster points, proper spacing of fuel sources from combustion units and other more elaborate considerations.

l Proposed plant layouts;

A choice of location for plant and layout play an important role on environmental impact. Hence, environmental impact assessment is a major part of GMP. Industries must be located at least 100M from closest residential quarter (depending of materials processed in plant).

l Flow diagrams for facility

For optimization and efficiency purposes, flow diagrams for complete refinery process are important for review with intent to ensure they conform to GMP

l Critical systems and areas

Some areas in a plant may require extra safety precautions in operations. The cGMP makes provision for such special considerations with the creation of customized set of operational guidelines that ensure safety and wellness of staff and environment alike.

cGMP EXAMPLE: FOOD PROCESSING PLANT

Outlined below are the cGMP considerations in the establishment and handling of a food processing plant.

Safety of Water

1. Process water is safe, if private supply should be tested at least annually.

2. Backflow prevention by an air gap or back flow prevention device. Sinks that are used to prepare food must have an air-gap.

Food Contact Surface

1. Designed, maintained, and installed so that it is easy to clean and to withstand the use, environment, and cleaning compounds.

2. If cleaning is necessary to protect against microorganisms, food-contact surfaces shall be cleaned in this sequence: wash with detergent, rinse with clear water, and then use an approved sanitizer. The sanitizer used shall be approved for use on food-contact surfaces. UA three-compartment ware washing sink or other equivalent methods shall be used for this purpose.

3. Gloves shall be clean/sanitary. Outer garments suitable.

Prevention of Cross-Contamination

1. Food handlers use good hygienic practices; hands shall be washed before starting work, after absence from work station, or when they become contamination (such as with eating or smoking).

2. Signs shall be posted in processing rooms and other appropriate areas directing employees that handle unprotected food, food-contact surfaces, food packaging materials to wash their hands prior to starting to work, after each absence from the work station, and whenever hands may become contaminated.

3. Plant design so that the potential for contamination of food, food-contact surfaces, or packaging materials is reduced to the extent possible.

4. Physical separation of raw and finished products.

Hand Washing Sinks and Toilet Facilities

1. Hand washing sinks, properly equipped, shall be conveniently located to exposed food processing areas. Ware washing sinks shall not be used for this purpose.

2. Adequate supply of hot and cold water under pressure.

3. Toilet facilities; adequate and accessible, self-closing doors.

4. Sewage disposal system shall be installed and maintained according to State law.

Protection from Adulteration (Food, Food Contact Surfaces, and Packaging Materials)

1. Food processing equipment designed to preclude contamination with lubricants, fuel, metal fragments, contaminated water, or other sources of contamination.

2. Food processed so that production methods to not contaminate the product.

3. Raw materials, works-in-process, filling, assembly, packaging, and storage and transportation conducted so that food is not contaminated.

4. Protection from drip and condensate overhead.

5. Ventilation adequate and air not blown on food or food-contact surfaces.

6. Lights adequately shielded.

7. Compressed air or gas mechanically introduced adequately filtered.

Scope of services

  • Engineering support
  • Representation of the construction owner (equipment, construction: supervision of general contractors, GMP concept draft)
  • Basic and detailed design
  • Support during the implementation phase
  • Clean room planning (incl. lab areas)
  • Construction management
  • Qualification
  • Validation support

Toxic Items: Labelling, Use, and Storage

1. Products used approved and used according to product’s label.

2. Sanitizer used on food-contact surfaces must be approved for that use.

3. Shall be securely stored, so unauthorized use is prevented.

Personnel Disease Control

1. Food handler, who has illness or open lesion, or other source of microbiological contamination that presents a reasonable possibility of contamination of food, food-contact surfaces, or packaging materials shall be excluded from such operations.

2. Adequate training in food protection, dangers of poor personal hygiene, and unsanitary practices shall be provided.

3. Management shall provide adequate supervision and competent training to ensure compliance with these provisions.

Pest Control

1. Management shall provide an adequate pest control program so that pests are excluded from the plant.

2. Program shall ensure that only approved pesticides are used and applied per the product’s label.

Plant Construction and Design

1. Walls, floors, and ceilings constructed so that they can be adequately cleaned and kept in good repair.

2. Adequate lighting provided.

3. Adequate ventilation or controls to minimize odours and vapours.

4. Adequate screening or protection of outer openings.

5. Grounds maintained free of litre, weeds, and pooling water.

6. Roads, yards, and parking lots maintained so that food is not contaminated.

Equipment

1. Equipment, utensils, and seams on equipment – adequately cleanable, properly maintained, designed, and made of safe materials.

2. Refrigerators and freezers equipped with adequate thermometer.

3. Instruments and control devices – accurate and maintained.

4. Compressed air or gas designed/treated so that food is not contaminated.

Equipment. Most equipment used to manufacture early GMP drug product is be managed under a qualification, preventive maintenance, and calibration program for the GMP facility. However, in early development, there may occasionally be a need to use equipment that is not part of such a program. Rather than performing a comprehensive qualification for a piece of equipment not expected to be frequently used, an organization may choose to qualify it for a single step or campaign. Documentation from an installation qualification/operational qualification (IQ/OQ) and or performance verification at the proposed operating condition is sufficient. For example, if solution preparation needs a mixer with a rotation speed of 75 rpm, then documentation in the batch record using a calibrated tachometer to verify that the mixer was operating at 75 rpm will suffice.

The use of dedicated or disposable equipment or product contact parts may be preferable to following standard cleaning procedures to ensure equipment is clean and acceptable for use. However, not all equipment or equipment parts are disposable or may have a substantial cost that makes disposal prohibitive. In that case, the product contact parts could be dedicated to a specific drug substance for use in drug product manufacture. Dedicating product contact parts to a compound may be costly and may be avoided in some cases by carefully considering product changeover and effective cleaning methods when purchasing equipment.

Another item to consider with respect to equipment, is that the more complicated the equipment is to run or maintain, the less desirable it might be for early GMP batches. In most cases, simple equipment is adequate and will uses less material and consume less total time for preparation, operation, and cleaning activities.

Weights and Measures

1. Scales used to measure net weight of contents shall be designed so they can be calibrated.

2. Products in interstate commerce – net weights/measurements also in metric.

 

CONCLUSION

Plant establishment is an activity that has kept rising from the inception of the industrial revolution until date. Giving rise to increase in raw material demand, increased pollution levels, higher energy demand, and overall greater economic output. As history and record keeping has served for an even longer period, it becomes necessary for adaptation to be made to avoid incidents and accidents that have occurred previously and also those that can be anticipated without actual devastating effect.

The development of the GMP is as a result of observed challenges in industry and environment over years of industrialization. It becomes necessary to upset these poor trends that have developed as a result of industrialization by so doing increasing the pros and reducing the cons.

GMP protects consumer, produce, equipment, and conserves the processes as a whole, leading to a more efficient sustainable process defining a new standard for yields and profit and eliminating the tendency of compromise made by industrialists to increase overall profits at the risk of staff and environment.

pilot pic 9

 

pilot pic 10

Batch documentation and execution

Batch record documentation preparation. Manufacturing documentation is a basic requirement for all phases of clinical development. 21 CFR Parts 211.186 and 211.188 describe master production and batch production records, respectively (7). The stated purpose of the master production record is to “assure uniformity from batch to batch.” Although the record assurance is important for a commercial validated manufacturing process, it does not necessarily apply to clinical-development batches. Material properties, manufacturing scale, and quality target product profile frequently change from batch to batch. Therefore, batch production records are the appropriate documentation for clinical trial supplies. Batch production records for Phase 1 materials should minimally include:

  • Name, strength, and description of the dosage form
  • A complete list of active and inactive ingredients, including weight or measure per dosage unit and total weight or measure per unit
  • Theoretical batch size (number of units)
  • Manufacturing and control instructions.

These minimum requirements are consistent with the FDA Guidance for Industry: cGMP for Early Phase Investigational Drugs, which requires a record of manufacturing that details the materials, equipment, procedures used and any problems encountered during manufacturing (2). The records should allow for the replication of the process. On this basis, there is flexibility in the manner for which documentation of batch activities can occur, provided that the documentation allows for the post execution review by the quality unit and for the retention of these records.

 

Batch documentation approvals. Review and approval of executed batch records by the Quality unit is required per 21 CFR Part 211.192 (7). This review and approval is required for all stages of clinical manufacturing. Pre-approvals of batch records should be governed by internal procedures as there is no requirement in CFR 21 that the Quality unit pre-approves the batch record (though this is highly recommended in order to minimize the chance of errors). Indeed, Table I shows that pre-approval of batch records by the Quality Unit is practiced by all 10 companies that participated in the IQ Consortium’s drug-product manufacturing survey related to early development. Batch records must be retained for at least 1 year after the expiration of the batch according to CFR Part 211.180, but many companies keep their GMP records archived for longer terms.

Room clearance. 21 CFR Part 211.130 requires inspection of packaging and labeling facilities immediately before use to ensure that all drug products from previous operations have been removed. This inspection should be documented and can be performed by any qualified individual.

Although line clearance for bulk manufacture is not specifically mentioned in the CFR, it is expected that a room clearance be performed. At a minimum, this clearance should be performed prior to the initiation of a new batch (i.e., prior to batch materials entering a processing room).

Hold time. During the early stages of development, final dosage form release testing confirms product quality and support establishment of hold times later in the clinical development. There is no requirement to establish hold times for work in process in early development. Specific formulation and stability experience, which is usually limited at this stage of development, should be leveraged to assess any substantial variations from expected batch processing times. The data gathered from these batches and subsequent development can be used to help establish hold times for future batches. (Exceptions to this approach may include solution or suspension preparations used in solid dosage form manufacturing, where procedures typically govern allowable hold times to ensure the absence of microbial contamination in the final product.)

Change control. Changes to raw materials, processes, and products during early development are inevitable. It is not required that these changes be controlled by a central system but rather may be appropriately documented in technical reports and manufacturing batch records. Any changes in manufacturing process from a previous batch should be captured as part of the batch record documentation and communicated to affected areas. The rationale for these changes should also be documented as this serves as a source for development history reports and for updating regulatory filings. The authors recommend that those changes that could affect a regulatory filing be captured in a formal system.

Process changes. Process parameters should be recorded but do not need to be predetermined because processes may not be fixed or established in early development. Given the limited API availability in early development, a clinical batch is often the first time a product is manufactured at a particular scale or using a particular process train. Therefore, process changes should be expected. Process trains and operating parameters must be documented in the batch record but changes should not trigger an exception report or CAPA. Changes should be documented as an operational note or modification to the batch record in real time. Such changes driven by technical observations should not require prior approval by the Quality unit, but should have the appropriate scientific justification (via formulator/scientist) or the appropriate flexibility built into the batch record to allow for the changes. This documentation should be available for Quality review prior to product disposition.

Calculation of yield. Actual yields should be calculated for major processing steps to further process understanding and enable optimization of processes. Expected yield tolerances are not always applicable to early development manufacture. At this stage of early development, when formulation and process knowledge is extremely limited, there may be no technical basis for setting yield tolerances and, therefore, this yield may not be an indicator of the quality of the final product.

In-process controls and R&D sampling. In-process tests and controls should follow basic requirements of GMPS to document consistency of the batch. For capsule products, these requirements may include capsule weights and physical inspection. For tablet products, compression force or tablet hardness and weights should be monitored together with appearance. R&D sampling, defined as samples taken for purposes of furthering process understanding but not utilized for batch disposition decisions, is a normal part of all phases of clinical manufacturing. In early development manufacturing, a sampling plan is required for in-process control tests, but not for R&D samples. However, for the purpose of material accountability, R&D sampling should be documented as part of batch execution. For these samples, testing results may be managed separately, and are not required to be included in regulatory documentation.

Facilities and equipment

Regardless of the scale of manufacturing, the facility used for manufacturing clinical trial supplies must meet the basic GMP requirements as described in the regulations and guidance documents. Below are three scenarios for early development and the advantages of each as pertaining to early development. The first involves a pilot plant facility designed and equipped for routine GMP operations. The second scenario aims to establish a GMP area within a laboratory environment. The third example focuses on conducting GMP manufacturing or leveraging the practice of pharmacy in close proximity to the clinical site.

GMP facility for drug-product manufacture. The traditional approach in GMP drug-product manufacture is to use a dedicated facility (often called a pilot plant) for early phase clinical trials. Advantages of this approach include that the quality systems for the facility (i.e., maintenance, calibration, cleaning, change management, CAPA, and documentation) are well defined, and that training and other activities required for maintaining GMP compliance are centralized. Other drivers to use a pilot plant in early development may be the need for specialized equipment, or larger batch sizes in special situations.

GMP area within a laboratory setting. In some cases, it may be advantageous to establish a GMP area within a “laboratory setting” (i.e., a drug-development facility not dedicated to the production of clinical supplies) for the manufacture of drug product in early development. The rationale for this approach might be to avoid the significant investment in setting up a dedicated facility and to create simpler, more flexible systems that meet GMP requirements but are tailored for the specific activity envisioned. Examples where this approach might be considered include the need for special containment not available in the pilot-plant; the need to work with radioactive or hazardous materials, use of controlled substances and the production of “one-off manufactured” product used for proof of concept. The business rationale should be documented and approved by the manufacturing and Quality groups. As long as the appropriate GMP controls are maintained, especially as related to operator safety, cleaning, and prevention of cross-contamination, there is no compliance barrier to using “lab-type” facilities for the manufacturing of early phase clinical batches. Before GMP manufacturing is initiated, however, a risk assessment should be conducted and documented. Inclusion of representatives from Quality, analytical, clinical manufacturing, product development, and environmental health and safety would be prudent. When selecting/designing an early development clinical manufacturing facility, consideration should be made for the receipt, storage, dispensing, and movement of materials. The manufacturing processes in the nondedicated area must protect the product, patient, and the manufacturing operators.

Additionally, companies should consider what items are appropriate for the manufacture. For example, the use of a certified laminar flow hood may be a better choice for manufacturing than a fume hood, because the former is designed to prevent contamination of the product, protect the operator, and the laboratory environment. In addition, with the appropriate cleaning, a laminar flow hood can more easily be used for multiple products. Small scale/manual equipment or procedures may be the best approach because the space is likely to be limited. With a small batch size, the use of small scale or manual equipment/procedures will minimize yield loss. Additional measures to be assessed include appropriate gowning and operator personal protection devices, area and operator monitoring for potent or radiolabeled drug exposure, and so forth.

Documentation of the facility preparation, product manufacture, and the return of the facility to the previous state, if needed, is recommended. This documentation should describe the rationale for the manufacture in the nondedicated area, risk assessment, preparation of the area, cleaning procedures, and list of responsible persons. This documentation can reference existing procedures or standard operating procedures (SOPs) along with documents associated with the meetings and preparation for the manufacture of the batch. Batch records and cleaning records should be part of the documentation and should follow the company’s data-retention policy.

Receipt and approval

Specifications. It is a GMP requirement that all raw materials for the manufacture of drug product have appropriate specifications to ensure quality. The compendial requirements should be used for setting specifications provided the material is listed in at least one pharmaceutical compendium (e.g., US, European, and Japanese Pharmacopeias). It is important that the use of materials meeting the requirements of a single compendium is acceptable for use in early phase clinical studies conducted in the US, Europe, and Japan. For example, a material that meets USP criteria and is used in the manufacture of a drug product should be acceptable for use in early clinical studies in the European Union. In the absence of a pharmaceutical compendium monograph, the vendor specification and/or alternative compendial specifications such as USP’s Food Chemical Codex should guide specification setting. In any case, the sponsor is responsible for the establishment of appropriate specifications. Therefore, it is the authors’ position that good practice is to have at least a basic understanding of the manufacture, chemistry, and toxicology of the materials to guide appropriate specification setting.

Material testing and evaluation. The minimum testing required for incoming materials is visual inspection and identification. However, as mentioned above, the appropriate tests should be determined for the material based on the knowledge of the manufacture, chemistry, and toxicology. If the vendor is qualified, then the certificate of analysis may be acceptable in conjunction with the visual inspection and identification testing (see “Vendor Qualification” section below).

Approval for use. Ideally, manufacture of a bulk drug product should begin with approved material specifications and with materials that are fully tested and released. However, there are circumstances where it may not be feasible to start manufacture with approved specifications and fully tested and released materials, including API. Manufacturing prior to final release (sometimes called manufacturing “at risk”) may be acceptable, however, because the quality system ensures that all specifications are approved, test results are within specifications, and all relevant documents are in place before the product is released for administration to humans. The “risk” must lie fully with the manufacturer and not with the patient.

Vendor qualification. Vendors supplying excipients, raw materials, or API must be qualified by the sponsor. Appropriate qualification should depend on the stage of development and an internal risk assessment. For, example if a vendor has a history of supplying the pharmaceutical industry and the material is to be used in early development, a paper assessment (e.g., a questionnaire) should be sufficient. If a supplier does not have a history of supplying the pharmaceutical industry, a risk assessment should be performed and depending on the outcome a site audit may be required prior to accepting material for use.

Ideally, vendors should be qualified prior to using raw materials for manufacture. However, it is acceptable for qualification to proceed in parallel as long as documentation/risk assessments are available prior to product release and as in the previous section all risk lies with the manufacturer and not the patient.

 

A production mixing unit is usually not geometrically similar to the mixer used for process development. Such differences can make scale-up from the laboratory or pilot plant challenging. A solution to these problems is to systematically calculate and evaluate mixing characteristics for each geometry change.

Geometric similarity is often used in mixing scale-up because it greatly simplifies design calculations. Geometric similarity means that a single ratio between small scale and large scale applies to every length dimension (see figure). With geometric similarity, all of the length dimensions in the large-scale equipment are set by the corresponding dimensions in the small-scale equipment. The only remaining variable for scale-up to large-scale mixing is the rotational speed — one or more mixing characteristics, such as tip speed, can be duplicated by the appropriate selection of a large-scale mixer speed.

Mixing Figure 1
The two most popular and effective geometric scale-up methods are equal tip speed and equal power per volume. Equal tip speed results when the small-scale mixer speed is multiplied by the inverse geometric ratio of the impeller diameters to get the large-scale mixer speed:

N2 = N1(D1/D2)

Equal power per volume involves a similar calculation, except the geometry ratio is raised to the two-thirds power:

N2 = N1(D1/D2)(2/3)

This expression for power per volume only applies strictly for turbulent conditions, where the power number is constant, but is approximately correct for transition-flow mixing.

Avoid mix-ups
As we have seen, taking successive steps allows the development of alternative solutions to scale-up. Similar methods can be used to scale-down process problems for investigation in a pilot-plant or laboratory simulation. Here, too, non-geometric similarity often is a problem. Such scale-down calculations should help pinpoint appropriate operating speeds to test in the small-scale mixer.
In any scale-up or scale-down evaluation, some variables can be held constant while others must change. For example, even with geometric similarity, scale-up will result in less surface per volume because surface area increases as the length squared and volume increases as length cubed. Similarly, keeping blend time constant rarely is practical with any significant scale change. Larger tanks take longer to blend than smaller ones. Also, Reynolds number is expected to increase as size increases. In addition, standard operating speeds or available impeller sizes may necessitate a final adjustment to the scale-up calculations.

Rules for scale-up always have exceptions but understanding the effects of scale-up, especially non-geometric scale-up, can provide valuable guidance. Indeed, appreciation of the tradeoffs involved in non-geometric scale-up may be crucial for success with large-scale mixing processes.

REFERENCES

1 https://docs.google.com/viewer?url=http%3A%2F%2Fwww.sunbio.com%2Fsub%2FSunbio%2520GMP%2520Capabilty.ppt

2 http://apic.cefic.org/pub/5gmpdev9911.pdf

3 http://www.pharmtech.com/early-development-gmps-drug-product-manufacturing-small-molecules-industry-perspective-part-iii?rel=canonical

“ICH Q7a. Good Manufacturing Practice for Active Pharmaceutical Ingredients” (Draft 6, October 19th, 1999, section 19).

“ICH Q6a. Specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances”.

“Good Manufacturing Practices for Active Pharmaceutical Ingredients” (EFPIA / CEFIC Guideline, August, 1996).

“Quality Management System for Active Pharmaceutical Ingredients Manufacturers” (APIC/CEFIC May 1998).

“Good Manufacturing Practices Guide for Bulk Pharmaceutical Excipients”, The International Pharmaceutical Excipients Council (October 1995).

“21 Code of Federal Regulations, parts 210 to 211”, U.S. Food & Drug Administration. “Guide to inspection of Bulk Pharmaceutical Chemicals”, U.S. Food & Drug Administration, (Revised Edition: May 1994).

“Guidance for Industry. ANDAs: Impurities in Drug Substances”, U.S. Food and Drug Administration, CDER (June 1998).

“Guideline on the Preparation of Investigational New Drug Products”, U.S. Food & Drug Administration, CDER (March 1991).

“EC Guides to GMP, Annex 13: Manufacture of Investigational Medicinal Products” (Revised Dec. 1996).

“GMP Compliance during Development”, David J. DeTora. Drug Information Journal, 33, 769-776, 1999.

FDA Guidance documents on internet address: http://www.fda.gov/cder/guidance /index.htm

EMEA Guidance documents on internet address: http://www.eudra.org.

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