Site Master File - LAW Services GmbH

Transcription

Site Master File
Version 04
Valid from
Valid until
02-01-2016
01-31-2017
L-A-W Services GmbH, Leipziger Arzneimittelwerk
Elisabeth-Schumacher-Str. 54/56
D-04328 Leipzig
Site Master File
Version: 04
Valid from: 02-01-2016
Page 1 of 2
Table of contents
Page
1.
General information about the manufacturer
1
1.1
Contact data of the manufacturer
1
1.2
Approved pharmaceutical manufacturing activities of the plant
1
1.3
Other manufacturing activities carried out in the plant
1
2
Quality management system of the manufacturer
2
2.1
The quality management system of the manufacturer
2
2.2
Approval procedure for finished products
3
2.3
Management of suppliers and service providers
5
2.4
Quality risk management (QRM)
7
2.5
Product quality reviews (PQR)
9
3.
Personnel
9
4.
Premises and equipment
10
4.1
Premises
10
4.1.1
Brief description of the heating and ventilation systems as well as the air conditioning
system (HVAC)
11
4.1.2
Brief description of the water systems
16
4.1.3
Brief description of other systems such as steam, compressed air, N 2 etc.
16
4.2
Equipment
17
4.2.1
List of the important equipment for the production and control laboratory
17
4.2.2
Cleaning and hygiene
17
4.2.3
GMP-critical computer systems
17
5.
Documentation
18
6.
Production
19
6.1
Type of products
19
6.2
Process validation
20
6.3
Material management and storage
21
7.
Quality control (QC)
25
8.
Sales, complaints, product defects and recalls
26
8.1
Sales (for the part in the field of responsibility of the manufacturer)
26
8.2
Complaints, products defects and recalls
26
9.
Self-inspection
27
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Annexe
no.
Annexe
1
Copy of the valid manufacturing authorisation
2
Page 2 of 2
Open part/
closed part
open part
with preparation list
closed part
List of the manufactured dosage forms including INN descriptions or the
conventional name (if available) of the active pharmaceutical ingredient (API)
used
--------------
Not applicable as a separate annexe: refer to annexes 1 and 4
3
Copy of the valid GMP certificate
4
List of the manufactured dosage forms including the active pharmaceutical
ingredient (API) used with the specification of the supply chains of outsourced
activities as well as
List of the contract manufacturers and contract laboratories including the
addresses and contact information
open part
closed part
open part
5a
Organisation chart
open part
5b
Number of employees in Quality Assurance, Production, Quality Control and
Storage
open part
6
Plans of the production areas including material and personnel flow, general flow
diagrams of the manufacturing processes for every product type (dosage form)
open part
- Site map of the premises
open part
- Floor plans
closed part
- Zone concept with machine installation
open part
- Personnel and material flow
open part
- Description of the ventilation technology
closed part
- Description of the laboratories
open part
7
Purified water (diagram of the water installation)
open part
8a
List of the important equipment for the production
open part
8b
List of the important equipment for the control laboratory
open part
9
Activities for which L-A-W Services GmbH Leipziger Arzneimittelwerk is certified
open part
10
List of the official GMP inspections of the last 5 years
open part
Site Master File
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1.
General information about the manufacturer
1.1
Contact data of the manufacturer
Page 1 of 27
L-A-W
Services
GmbH,
Leipziger
Arzneimittelwerk,
Elisabeth-Schumacher
Str.
54/56,
04328 Leipzig, originates from “Homöopathischen Centralofficin Dr. Willmar Schwabe” established in 1866
and is domiciled in the manufacturing company set up in 1926 for purposes of industrial production of homoeopathic products in Leipzig Paunsdorf. After passing through different legal forms in the GDR, independent
existence as Leipziger Arzneimittelwerk GmbH in the Federal Republic of Germany (1990) and takeover by
the Wyeth Group (1992), Leipziger Arzneimittelwerk belonged to RIEMSER Pharma GmbH since March 2000
as a plant. Since, 01.06.2013 the location is operating as an independent company after change in ownership
of the Leipzig plant and associated with that, the transition of the company and personnel in accordance with
§ 613a of BGB (German Civil Code) into L-A-W Services GmbH, Leipziger Arzneimittelwerk.
L-A-W Services GmbH, Leipziger Arzneimittelwerk manufactures solid, semi-solid and liquid pharmaceuticals,
medical device, dietary supplements, cosmetics and API (active pharmaceutical ingredient) on a contract basis. Human as well as veterinary medicinal products are manufactured.
Contact data:
L-A-W Services GmbH, Leipziger Arzneimittelwerk
Elisabeth-Schumacher-Str. 54/56
04328 Leipzig
Germany
Telephone: +49 341 2582-0 (06:00 hours to 20:00 hours)
Fax:
+49 341 2582-444
GPS data of the plant:
Length:
12° 26’ 22’’ E
Width:
51° 21’ 04’’ N
1.2.
Approved pharmaceutical manufacturing activities of the plant
Only the pharmaceutical activities mentioned in the manufacturing authorisation are carried out.
Copy of the valid manufacturing authorisation (refer to annexe 1)
Type of the products currently manufactured in the plant (refer to annexe 1 or 4 (closed part)
List of the official GMP inspections of the plant (refer to annexe 10)
1.3
Other manufacturing activities carried out in the plant
Non-pharmaceutical manufacturing activities: manufacturing of cosmetics, dietary supplements, medical devices and chemicals.
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2.
Quality management system of the manufacturer
2.1
The quality management system of the manufacturer
Page 2 of 27
L-A-W Services GmbH, Leipziger Arzneimittelwerk, operates a quality assurance system on the basis of the
EU GMP Guideline on Good Manufacturing Practices for pharmaceuticals.
The quality assurance system helps to ensure the quality of the pharmaceutical products expected by the
customers as well as to implement the quality objectives of the company comprehensively in all the company
departments.
The principle of the quality policy is that every work step is a contribution to the quality of the end product and
must hence possess the required quality itself. This objective is ensured through corresponding framework
conditions such as suitable technical and organisational equipment, qualified personnel, etc.
The quality assurance system comprises all the company departments. It has been defined in SOPs, operating
instructions and other documents and consists of the following elements among others:
 Current documentation system (refer to Chapter 5)
 Personnel training, job descriptions
 Hygiene
 Self-inspections
 Supplier qualification including subcontractor
 Qualification of systems, equipment and areas
 Calibration of measuring equipment
 Maintenance of areas, systems and equipment
 Monitoring of environmental conditions
 Validation of manufacturing, cleaning and test processes
 Change control, deviation, OOS and CAPA management
 PQR
 Inspection and manufacturing in accordance with approved instructions
 Release procedures
 Processing of complaints
The Quality Assurance department is responsible. The Head of Quality Assurance leads the department (refer
to organisation chart annexe 5a).The Quality Assurance department directly reports to the Management Board.
The Management Board is involved in the quality management in different ways and is constantly informed of
the integration into QA committees, a structured reporting system as well as through the inspections of the
Quality Assurance department generally conducted once a year. Other options to obtain information are the
protocols of the regular quality assurance meetings conducted every 14 days as well as the reports of audits
and self-inspections as well as monthly reports to the Management Board.
The other departments of the company are also responsible for maintaining the QM system. They are stated
in the respective job descriptions as well as in the valid SOPs and instructions.
An important committee for promoting and ensuring the collaboration of all the departments in this regard is
the QA consultation that is conducted regularly every 14 days.
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L-A-W Services GmbH, Leipziger Arzneimittelwerk is certified for the following activities:
 Manufacturing and testing of pharmaceuticals for human use, monitoring by the Landesdirektion Sachsen
 Manufacturing and testing of pharmaceuticals for animal use, monitoring by the Landesdirektion Sachsen
 Manufacturing and testing of investigational medicinal products, monitoring by the Landesdirektion Sachsen
(For more information, refer to annexe 9)
Furthermore:
The appropriate specifications in accordance with DIN EN ISO 13485:2012 are considered for manufacturing
and testing medical devices of class I and IIa. A certification is not available at present.
The manufacturing and testing of dietary supplements, dietary/ balanced foodstuffs and cosmetics is monitored
by the Saxony Regional Office. The cosmetics are manufactured and tested taking into account DIN EN ISO
22716 “Cosmetics – Good Manufacturing Practices (GMP) – Guidelines on Goods Manufacturing Practices”.
2.2
Release procedure for finished products
The Qualified Person, in accordance with § 14 AMG, having the expertise necessary in accordance with § 15
AMG is responsible for releasing the pharmaceuticals and investigational medicinal product, for placing them
on the market. He reports directly to the Management Board and has all the necessary powers for carrying out
this work.
The tasks and responsibilities are specified in writing in a corresponding job description of the Qualified Person.
Multiple Qualified Persons have been nominated in accordance with § 14 AMG for L-A-W Services GmbH,
Leipziger Arzneimittelwerk. The Qualified Persons are completely recorded by name and listed in the organisation chart – annexe 5a. The Qualified Person mentioned first takes the responsibility for the tasks of the job
holder on a full-time basis. If he is unable to attend, the persons following in the list are representatively responsible for it and will act correspondingly.
The QM system is adapted to the needs of the batch release.
All the finished products are in the quarantine status until the dispatch release, release for placing on the
market or another decision. This status is secured by the identifications and configurations in the EDP (ERP
system) as well as by a physical identification with the help of supply notes with the pallets.
Manufacturing and testing must be carried out and logged in accordance with the manufacturing instructions
or testing instructions. All deviations in the process and from the regulations in the specification must be documented and investigated thoroughly. After inspecting the manufacturing documents, the Head of Manufacturing, in accordance with § 12 of AMWHV (Regulation for the manufacturing of pharmaceuticals and APIs),
must confirm proper manufacturing and labelling of the batch corresponding to the manufacturing instructions.
The Head of Quality Control, in accordance with § 12 of AMWHV, must confirm that the testing was conducted
corresponding to the testing instructions and the batch possesses the proper quality.
The Qualified Person is responsible for ensuring that every batch of the pharmaceutical was manufactured
and tested in accordance with the trade of pharmaceuticals. He has to confirm the compliance with the regulations for every pharmaceutical batch in a serial list before placing them on the market. For assuming his
responsibility as a Qualified Person in accordance with AMG § 14, the job holder has to rest on the expertise
of and information from the function holders - Head of Manufacturing as well as Head of Quality Control (§ 12
Para. 1 of AMWHV Manufacturing Management and Quality Control Management). He can moreover rest on
certificates, which have been issued by other Qualified Persons if the batch has passed through different steps
of manufacturing and testing or parts of these at different locations or with different manufacturers.
The Qualified Person actively has to examine the batch documentation and the batch record review and take
it into consideration. Furthermore he has to take into account essential information, especially that which is not
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included in the manufacturing and testing documents, and he has to evaluate it. If necessary, he has to use
the certificates issued by other Qualified Persons for deciding on the release of the finished product batches.
The Qualified Person certifies that the pharmaceutical has been manufactured in accordance with GMP and
the registration documents. This is followed by the release and entry in the release register or, in some cases,
another decision. The release or another decision is indicated on the product and in the EDP. Rejected products will be stored separately and under lock and key, in an isolated manner and with the corresponding physical identification. The blocking will also be saved in the EDP system.
The release procedure is defined in the SOP for batch release of finished products. The release for putting the
pharmaceutical batches and investigational medicinal products on the market and also the variant of the dispatch release of aforementioned finished products as well as the releases for dispatch of non-pharmaceuticals
are described there, too.
Furthermore, SOPs are available, which describe how to deal with deviations and out-of-specification results.
The system for activities that have been ordered is also stipulated in SOPs.
Another SOP describes the procedure for dealing with rejected products.
Quarantine and release of the finished products, conformity with the registration
The release is regulated in the underlying contract for classifying the pharmaceutical responsibility between
the customer and L-A-W Services GmbH Leipziger Arzneimittelwerk as the contractor.
The finished products are released in accordance with the corresponding SOP. All the finished products remain
in quarantine until they are released. The following processes are distinguished between:
 Release of finished medicinal products and investigational medicinal products for putting them on the market in accordance with §16 of AMWHV as well as in accordance with Annex 16, 2001/83/EC as well as
2001/82/EC for finished medicinal products and in accordance with Annex 13 2001/83/EC for investigational medicinal products.
The release by the Qualified Person is issued after review of the entire, completed documentation about
the manufacturing and quality control approved by the relevant employees. This includes properly signed
manufacturing and packaging logs, inspection logs and the batch record review. If individual steps in the
order are carried out at third party plants, the manufacturing and inspection logs and, if applicable, certificates of conformity of the contract manufacturer or laboratories serve as a basis for the release decision.
Within this scope, the recourse to other QPs is also possible. On the basis of this and consideration and
evaluation of other essential and relevant factors and information – consideration of essential information a statement is made by the Qualified Person regarding the release (or another decision as regards the
status) with a date and signature. The inspection and confirmation of the conformity with the registration
documents is also a part of the release decision made by the expert. The release decision will be documented by the Qualified Person in a serial list and on the corresponding form that is part of the batch
documentation.
 Release for dispatch
If the pharmaceutical responsibility for the batch release for putting on the market lies with the customer in
case of contract manufacturing by L-A-W Services GmbH (contractor), a certificate of compliance (CoC)
will be issued in accordance with Annex 16 EU-GMP by the Qualified Person and the release for dispatch
will be confirmed.
Batch recall
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If pharmaceutical batches released by LAWS for putting on the market are subsequently recalled, this must
be noted in the serial list in accordance with the requirement of § 17 Para. 5 of AMWHV. This means stocktaking of that what could have been on the market, and recording of the batch recall in the list by the Qualified
Person.
Statement on control strategies
It is confirmed that process analytical technologies (PAT) and / or real-time releases or parametric releases
do not play any role within the scope of the control strategies.
2.3
Management of suppliers and service providers
A system for qualifying the GMP-relevant suppliers/service providers is installed and described in SOPs, which
includes the identification of the supply chain and also an audit system.
It contains the entire life cycle of the suppliers:
Planning/selection
Risk management system
Risk assessment
First qualification/release
Supply/monitoring
Periodic assessment/ requalification
Blocking
Based on a risk analysis, and taking into account the following safety objectives
 pharmaceutical or GMP objectives,
 occupational health, safety and environmental protection as well as
 business or economic objectives
the suppliers will be allocated to a risk class as well as the scope and content of the qualification will be defined
in detail.
The qualification must have been completed with a release before the order is given to GMP-relevant contractors or suppliers.
After a monitoring phase, a requalification/assessment takes place, which can also end in a blocking.
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Lists of the released contractors, suppliers of raw materials as well as other suppliers and service providers
will be maintained in the QA department and are available to the departments, especially the Purchasing /
Procurement department for consideration and compliance.
Owing to their significance for the quality of the products manufactured, the contract manufacturers / contract
laboratories as well as the suppliers of raw materials (active pharmaceutical ingredients, additives and packaging containers) are thereby especially singled out.
The release of contract manufacturers/ contract laboratories mainly requires the following prerequisites:
 Existence of the prerequisites for providing the required service
 Availability of a valid manufacturing authorisation/ GMP certificate
 Availability of an audit report
 Availability of a contract about the classification of the pharmaceutical responsibility.
The Quality Agreement contains detailed regulations regarding the responsibility for procuring the raw materials, the manufacturing, testing and/or release of the relevant product. Moreover, the contract contains regulations for processing complaints, qualifying suppliers, generating the PQR, conducting the stability tests as well
as forwarding information in case of changes and deviations.
The manufacturing and testing regulations of the contractor will be checked and approved by the relevant
persons of L-A-W Services GmbH against the registration documents or against the master regulations allocated by the customer and taken as a basis in the approval. The approval will be additionally obtained by the
customer of L-A-W Services GmbH.
The contractor is under an obligation to follow and adhere to the GMP regulations and gets them certified from
the relevant Qualified Person (CoC).
The contractor is under an obligation to allocate sub-contracts only after an approval by L-A-W Services GmbH
so that updated information about the supply chain is available at all times.
The contract manufacturers and contract laboratories are specified in annexe 4 (closed part).
The qualification of suppliers of raw materials proceeds across multiple stages and involves all the parties in
the supply chain (manufacturer and trader).
The supplier must have been approved by the Quality Assurance department before an initial order. The basis
of the release decision is the availability of sample test results, supplier certificates, other product information
(specifications, certificates, statements about TSE / BSE, solvent residues, REACH among others if necessary) as well as information, certificates and documents of traders and manufacturers such as questionnaires,
proofs and information regarding the QM system and audit reports, if notified to be necessary. In addition to
the Quality Assurance department of the customer and the internal departments, Purchasing/Procurement,
the Manufacturing and Quality Control departments are also involved functionally and as regards content.
After three goods receipts at the earliest, the supplier shall be assessed and will result in the supplier (the
source of supply) being allocated to a supplier class. Depending on the allocation, the incoming tests can then
be reduced according to defined specifications, whereby a full test must be conducted regularly in accordance
with the specifications.
Audits at contractors and suppliers of raw materials are planned once a year.
The execution and documentation of audits as well as their frequency is defined in a SOP.
Audits of contract manufacturers and contract laboratories are necessary before the release and then generally
every three years.
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Audits of raw material suppliers will be conducted in a risk-based manner, whereby, among other things, the
availability of GMP certificates or other certifications of the QM system, the material type (API) as well as the
variety and quantities of the materials procured by this supplier will be considered.
It is possible to resort to audits conducted by third parties.
When delivering raw materials, the manufacturer and trader will be audited for compliance with the specifications and the released supply sources within the scope of the incoming inspection.
In case of suspicion of imitated/ falsified products, the delivery will be immediately rejected, the supply chain
will be inspected and informed and the relevant authorities will be informed as well.
Imitated/ falsified products can be identified with the help of the measures established in the company.
The collaboration with our suppliers even lasts many years in some cases and is characterised by a good bond
of trust. The Purchasing department stays in close contact with our suppliers so that discrepancies in a delivery
could also be identified in this manner, which would have cropped up due to infiltration of falsified products in
the supply chain.
All the goods receipts of raw materials (packaging material, active pharmaceutical ingredients, excipients, bulk
products) will be checked by the Quality Control department at least for identity, depending on the specifications regarding the type and scope of the incoming inspection. In this connection, the sound condition of the
packaging, if available, the proper and intact lead-sealing as well as the compliance of the specifications on
labels and delivery notes with the approved supplier will also be checked.
If the raw materials are procured by L-A-W Services GmbH, the quality is and will also be checked and ensured
in accordance with the specifications of the incoming test.
If the raw materials are provided by the customer, the quality is considered to be warranted. During goods
receipt, the identity will be checked and ensured by the Quality Control department as described above. Deviating regulations are possible in accordance with the specifications and in agreement with the customer.
Use of external scientific, analytical or other technical support for manufacturing and analysis (refer to annexe
4 closed part).
List of the manufactured dosage forms including the active pharmaceutical ingredient (API) used with the
specification of the supply chains of outsourced activities as well as list of the contract manufacturers and
contract laboratories including the addresses and contact information (refer to annexe 4 closed part).
The responsibility for compliance with the registration documents is defined in the Quality Agreement and is in
the role of the customer. This is ensured with the approval of the testing and manufacturing instructions by the
customer as well as continuous information to our Qualified Person about the current status of the registration
and about corresponding changes or in accordance with the contractual regulations and pharmaceutical responsibility classification in the agreed type and scope.
2.4
Quality risk management (QRM)
The risk management system, which is installed within the scope of the quality management system, includes
all the areas of manufacturing and testing pharmaceuticals and other product classes and helps to ensure the
quality of the pharmaceuticals manufactured and other product classes as well as the ability to deliver on
schedule.
Risk analyses are predominantly conducted in the form of informal risk inspections, fish-bone diagrams and
based on FMEA. The execution of FMEA-based risk analyses is defined in a SOP.
GMP-risks in particular and risks for the quality of the pharmaceutical or for the patient associated with it are
considered in this respect, but also technological, financial, time-related and financial risks with an effect on
the company or the ability to deliver as well as health risks for the employees of the company.
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In addition to QA, QP, Head of Manufacturing and Head of Quality Control, the heads or employees of the
relevant departments are included. The Management Board will either be directly included or informed during
discussions or by means of minutes of the consultation depending on the requirement.
When defining the processes in SOPs, the elements of the risk management system to be used including
responsibility and employee group to be included/ informed will also be defined and described:
 Risks at the time of manufacturing and testing will be considered and minimised with the following activities:
qualification of the equipment during manufacturing and quality control including supply systems, qualification of the manufacturing and storage areas taking into account the required climatic conditions, validation
of the processes for manufacturing, testing and cleaning, qualification of suppliers and service providers,
employment of qualified and trained personnel. The type and scope of the tests to be conducted will be
defined based on the risks. Risk analyses will be conducted in accordance with the specifications.
 The temperature and, if necessary, humidity monitoring in the storage and manufacturing areas is based
on temperature mapping for ascertaining the critical measuring points. Monitoring will be implemented by
a central climate monitoring system with integrated recording and alarm system.
 Environmental monitoring will also be carried out in a risk-based manner; the measuring points will be
defined within the scope of the qualification.
 In order to identify the risks at an early stage, intervention limits were defined in the form of warning and
alarm limits as well as specification limits and trend and other data analyses will be generated.
 The allocation of the line on which solid preparations are to be packaged, is carried out on the basis of a
risk analysis.
 The audit programme for suppliers and subcontractors will be prepared in a risk-based manner.
 The changes, deviations, OOS and complaints will be processed taking into account the risk inspections.
 The goods receipts will be tested based on the risks. The testing scope will be defined depending on the
qualification status of the supplier.
 The stability tests will be defined taking into account the valid regulations and in a risk-based manner (matrixing, bracketing).
 The training programme will be defined risk-based.
 The decisions of the QP are based on the information about the manufacturing and testing as well as the
information associated with it and are also risk-based.
The measures defined in the risk analysis will either be processed in the process to which the risk analysis
belongs or transferred to the CAPA system of L-A-W Services GmbH.
Risks will also be considered when defining processes, which must not contain any risk inspections.
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2.5
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Product quality reviews (PQR)
Regular product quality reviews (PQR) will be carried out for all the pharmaceuticals manufactured/ tested/
released in the company after order by the respective customer and in a manner and scope agreed by both
parties. These reviews will be prepared by the Quality Assurance department in accordance with the specifications of the valid SOP. Furthermore, the requirements of the customer will be taken into account.
The PQR will be carried out product-related for a defined period – generally a year –, but should include a
minimum of five bulk product batches. If less than five bulk product batches are manufactured within a year,
the period under review can be extended correspondingly in order to have the required minimum number of
batches at disposal.
If a period of 3 years has passed since the last period under review, a PQR should be prepared irrespective
of whether 5 bulk product batches have been reached. In case of less number of batches (< 3 batches in the
period under review of 3 years), the scope and contents of the PQR must be adapted in a risk-oriented and
purposeful manner. Inappropriate sections or parts can be omitted fully or in part with justification.
The report also includes all the manufactured batches, i.e. even those which were rejected and destroyed.
The information, changes and dependencies, which cropped up during the period under review when manufacturing and testing the product, will be recorded, evaluated and documented within the scope of the PQR.
The aim of the PQR is to check the consistency of the process and the suitability of the specifications for the
raw materials and packaging materials as well as for the finished product. With the PQR, the Qualified Person
is provided with another tool to ensure the pharmaceutical quality of the product within the scope of the release.
3.
Personnel
Organisation chart (refer to annexe 5a)
Number of employees in the departments (refer to annexe 5b)
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4.
Premises and equipment
4.1
Premises
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The plant premises are in Leipzig-Paunsdorf in the “Hohentichelnstraße/ Permoserstraße” industrial area. The
plant premises is bordered in the south and west by Permoserstraße or Elisabeth-Schumacher-Straße, other
companies in the north and east of the plant premises (snack bar or warehouse).
Size of the company:
approx. 3.85 ha
Main building:
Year of construction - 1926
Extension - 1938
Addition of stories in the south wing - 1990
Modernisation 1990 – 1996
Laboratory extension - 2007
Partial modernisation for the GMP-compliant remodelling including ventilation technology - 2009 to 2014
Built-up area: 5110 m², 1- to 4-storey
Manufacturing and/or packaging of solid, semi-solid and liquid products;
Storage, laboratory, management, workshop, utilities management, canteen, sanitary areas
Annexe:
Built-up area: 561 m², 2-storey
unused at present
Warehouse:
Year of construction 1983, new flooring 2008
Built-up area: 1779 m²
Installations: High-bay racking, office containers
Storage of hazardous
materials:
Storage/forklift garage:
Storage for rejected for packaging material and finished products
Storage shed:
Year of construction - 1981/83
Transformer station:
Detached house:
Covered storage area:
Built-up area: 553 m2
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Fuel oil tank depot:
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Capacity: 4x24 m³
The manufacturing for different markets is not carried out in different buildings.
The position of the building in the premises is shown in annexe 6.
Position, size and utilisation of the rooms in the manufacturing area including storage rooms, material and
personnel flow as well as the classification of the rooms are shown in annexe 6.
L-A-W Services GmbH Leipziger Arzneimittelwerk manufactures products, which contain substances, which
are allocated to the toxic and hazardous categories (refer to section 6.1).
Areas for storing and handling highly toxic, hazardous and allergenic substances:
Microbiological laboratory:
Reference strains of risk class 2 as per IfSG
Storage of hazardous
materials:
Storage of the hazardous materials as per VbF
Storage for active pharmaceutical ingredients with
risk potential:
Storage of active pharmaceutical ingredients with risk potential
Safety weighing workstation:
Weighted sample and suspension of substances, which are classified as toxic
and/ or hazardous
Bulk manufacturing:
Processing of active pharmaceutical ingredients and other substances with the
above mentioned risk potential (pre-suspended; see above)
Blister room 1:
Blistering
of
solid
forms
with
less
therapeutic
(exposed formulations, whose lowest therapeutic dosage is ≤ 10 mg)
index
(Also refer to section 6.1)
The cold storage cell has special storage conditions with two areas at 2 °C to 8 °C as well as 8 °C to 15 °C.
4.1.1
Brief description of the heating and ventilation systems as well as the air conditioning system (HVAC)
Separate ventilation systems are operated for the different product areas as well as for the sanitary areas. The
ventilation systems are adapted to the special requirements as regards their features.
Only the special features of the individual ventilation systems for the manufacturing and quality control areas
are described below.
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Main building – semi-basement:
Ventilation system 1
refer to annexe 6
Bulk manufacturing 1 (R1033), bulk manufacturing 3 (R1034), weighing cabinets (R1030 – 1032): refer to
annexe 6
heated, cooled
Implementation of clean room class E
Proportion of ambient air: minimum 30%
Ventilation number 5 - 10
Supply air via H13
Extraction system for gel manufacturing (connectable if necessary)
Pressure gradient LTA 1:
- R1027, R1028, R118B as clean corridor in excess pressure to the black zone
- R1027, R1028 as clean corridor in low-pressure of 5 Pa to adjacent corridor R188
- Corridor R188 in excess flow of 3 Pa to corridor R118B (LTA 1)
- Clean corridor equal pressure to adjacent corridor R188 (LTA 37)
- Pressure drop from clean corridor to bulk manufacturing 1 and 3 of 5 Pa
- Pressure drop from clean corridor to personnel air lock 118A of 5 Pa
- Pressure drop from clean corridor to weighing cabinets 1-3 and safety weighing workstation of 10 Pa
Safety weighing workstation
Two workstations
Air velocity at the weighing workstation (right)
Air velocity in the weighing cabinet (left)
0.15 m/s 100% supply air H14
0.45 m/s recirculating air via H14
refer to annexe 6
Bulk manufacturing 2
heated, cooled
Proportion of ambient air: 100% (via building envelope)
Ventilation number in the subareas: 5 - 10
Excess pressure to black zone
Pressure gradient to upstream clean corridor (LTA 37)
Supply air via H13
refer to annexe 6
Bulk manufacturing 4
heated, cooled
Ventilation number in the subareas: 10-20
Excess pressure to black zone
Pressure gradient to upstream clean corridor (LTA 37)
Supply air via H13
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Ventilation system 22:
refer to annexe 6
Container cleaning/container drying area
heated
Recirculating air-dehumidification system in the room
Ventilation number in the subareas: 10
Pressure gradient as a directed overflow from the container drying area in the direction of the container cleaning
Supply air via F9
Cold storage cell in the raw materials warehouse
two-tier: 2 °C to 8 °C and 8 °C to 15 °C
Implementation of no clean room class
Heating cell in the warehouse for opened containers
up to 60 °C
refer to annexe 6
Sampling cabinet - quality control
Proportion of ambient air: 100% (from building envelope)
Ventilation number in the subareas: 5 – 10
Excess pressure barriers in the locks as against the black zone of +10 Pa and as against the sampling room
of +5 Pa
Supply air via third filter step H14
Vacuum cleaner in the sampling cabinet for spot extraction via H13
refer to annexe 6
warehouse for opened containers, bulk products warehouse, central materials lock, cleansing agent area and
adjacent areas (R1010 to 1025):
heated, cooled, partly dehumidified
Proportion of ambient air: 100%
Supply air via third filter step H13, additional filter-fan-units for filtration of recirculating air with H14 in R1010,
R1020, R1024, R1025
Additional vacuum-cleaning units in the central materials lock and dedusting of the warehouse for opened
containers
Pressure gradient LTA 37:
- Bulk products warehouse, weighing corridor, vestibules for bulk manufacturing 2 and 4, container
cleaning corridor as clean corridor in excess pressure to black zone; gradual reduction in pressure via
the materials lock, personnel air lock R189 and cleansing agent warehouse twice 5 Pa
- Clean corridor with an excess pressure, respectively excess flow of 5 Pa to adjacent LTA 1
- Pressure drop from clean corridor to:
 bulk manufacturing 2 of 5 Pa
 Bulk manufacturing 4 of 5 Pa
 Sink and ZBV room of 10 Pa each
- Directed overflow from clean corridor via container cleaning and container warehouse provision in the
direction of container cleaning (LTA 22)
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Exhaust air implementation for vertical conveyor; directed overflow from bulk products warehouse and
container cleaning provision as well as from packaging 1 in the direction of the vertical conveyor with
clean room class F
refer to annexe 6
Central personnel air lock
heated, cooled
Lock area for clean room class E
Pressure gradient from the clean room via the lock rooms to black zone of twice 5 Pa
Supply air via F9
Main building – ground floor:
refer to annexe 6
Packaging 1 and locks
heated, cooled, moistened
Implementation of clean room class F
Ventilation number: 6
Excess pressure red. 5 Pa, overflow to the black zone
Supply air via F9
independent laminar flow boxes via the filling and closing machines for semi-solid products (min. H13)
refer to annexe 6
Blister room 1 (enclosed blister line)
heated, cooled, moistened, dehumidified
Air exchange rate min. 15x in blister room 1, min. 10x in the material locks and personnel air locks, low pressure as against packaging, two-tier via locks of ≥ 15 Pa
Supply air via F9
additional local extraction system at the blister machine via H14
multi-stage locking procedures (physical barriers and air shower)
refer to annexe 6
Blister room 2 (enclosed blister line)
heated, cooled, moistened, dehumidified
Air exchange rate min. 15x in blister room 2, min. 10x in the material locks and personnel air locks, low pressure as against packaging, two-tier via locks of ≥ 15 Pa
Supply air via F9
additional local extraction system at the blister machine via H13
single-stage locking procedure
Filling rooms liquid/ semi-solid 1 and 2
heated, cooled
refer to annexe 6
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Supply air 100% from packaging 1 (room 236) via H14
Air exchange rate min. 10x in bottling rooms 1 and 2
Excess pressure in the bottling rooms 1 and 2 min. 10 Pa
Reduction in pressure via materials lock and personnel air lock, excess pressure in the locks min. 5 Pa
refer to annexe 6
Cleaning area
heated, cooled
Supply air 100% from packaging 1 (room 236) via F9
Air exchange rate min. 10 in the cleaning room (room 265)
Flow direction from storage (room 276) to the cleaning and packaging 1 rooms as well as from packaging 1
via provision (room 289) to cleaning
refer to annexe 6
Packaging 2 and 3
heated, cooled
Proportion of ambient air 100%
Ventilation number: 15 (locks 5)
Excess pressure in the locks as against manufacturing room as well as black zone of 5 - 15 Pa
Supply air via F9
Local extraction (H13)
Galenic laboratory
heated, cooled
Proportion of ambient air 100%
Supply air via F9
Lab hood independent of the ventilation system
refer to annexe 6
Quality control laboratory
heated, cooled
Temperature regulation separate for every room
Supply air via F9
2 lab hoods, independent of the ventilation system
Microbiology laboratory
Supply via ventilation system, quality control laboratory
depending on clean room class E
Supply air via H14
Microbiological safety cabinet class 2 in accordance with DIN 12950; independent of the ventilation system
Main building – attic storey
Attic storey laboratory
heated, cooled
refer to annexe 6
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Supply air via F9
Lab hood, independent of the ventilation system
Compliance with the parameters defined in advance with respect to air supply, air refeeding, temperature,
humidity, pressure differences and air exchange rates will be checked and ensured within the scope of the
qualification of the ventilation system and the room. The parameters will be further monitored within the scope
of monitoring, maintenance procedures and requalifications.
4.1.2
Brief description of the water systems
Purified water, which is produced by means of reverse osmosis, is used for the manufacturing (refer to annexe
7).
Drinking water as well as purified water are used for cleaning.
The drinking water is extracted from the public drinking water network of Kommunale Wasserwerke Leipzig
GmbH.
In addition, other water treatment plants are available for galenics (only for development purposes) and in the
quality control laboratories.
The laboratory water production from drinking water is carried out using an ion exchanger with special treatment systems.
The HPLC water production is carried out by means of reverse osmosis with a downstream high-purification
column und sterile filter.
The system for producing purified water (reverse osmosis system) is shown in annexe 7 as a schematic representation. It has an output of 1000 l/h.
The drinking water is pre-treated using a pre-filter having the pore size 0.5 µm and 0.45 µm and ultraviolet
lamp. The quality of purified water is subsequently achieved in the two-tier reverse-osmosis system.
The conductivity is monitored online. If the limit value is exceeded, the water is not carried to the extraction
cycle.
The ring line is equipped with a container, pump, cooler and heater and provides the purified water to 6 extraction points for manufacturing and cleaning.
The water is stored without any loss in quality by means of cooling and constant recirculation.
The ring line with all the fittings is regularly sanitised by means of heating in accordance with the SOP.
The quality of the water produced is, on the one hand, ensured with the qualification of the system that has
already taken place and, on the other hand, by means of continuous monitoring.
The sampling points for the monitoring and the inspection frequency are defined in SOPs.
The purified water to be used during manufacturing is monitored by inspection of the chemical and microbiological criteria by the Quality Control department.
4.1.3
Brief description of other systems such as steam, compressed air, N 2 etc.
A compressed air system is operated, which provides compressed air to the laboratory department as well as
to the manufacturing department - compressed air not in contact with the product (system control) as well as
compressed air in contact with the product.
Other systems are not operated at the plant. Required gases are directly taken from cylinders.
The required compressed air is centrally generated for the entire manufacturing department and laboratory
department and supplied via an internal network.
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The compressed air is mainly generated using a screw compressor from Boge, type VLKEX 22R-8. Two piston
compressors from Boge of the RM 3700-313 type serve as supporting compressors in times of high loads. The
generated compressed air (10 bar) is buffered in two compressed-air chambers having a capacity of 1000
litres each. An oil/ water separation takes place before the drying stage. A filter stage consisting of two compressed air filters of the ECOCLEAN type is allocated to the compressed air dryer of the BOGE DS 75 230/1/50
BEKO 32 type. After the compressed air drying, 2 filter batteries, consisting of 3 filters each of the Domnick
Hunter make (reversible in case of charging), are again integrated into to outgoing central compressed air line.
The operating pressure is reduced from 10 bar to the required pressure stage directly on the machine or in
case of the consumer.
The process systems of the bulk manufacturing 1 – 4 are connected to a central nitrogen supply. The nitrogen
is provided in compressed gas cylinders, which are connected to a central station. The required line pressure
is set at this station and the nitrogen is distributed to the process systems. Compressed air and nitrogen is
switched between at the process systems at the time of acceptance.
4.2
Equipment
4.2.1
List of the important equipment for the production and control laboratory
List of the important equipment for the production and the quality control (annexes 8a and 8b).
4.2.2
Cleaning and hygiene
The cleaning of surfaces of machines and equipment that are in contact with the product is described in detail
in the corresponding operating instructions. The contents of the operating instructions and the development of
cleaning procedures are defined in a SOP. Cleaning-in-place procedures will be preferably used. If this is not
possible, the cleaning will be done manually with visual dual inspection of the cleaning result. The cleaning
procedures are validated. The validation procedure is described in a SOP.
The room cleaning and personnel hygiene are described in the hygiene plan. Microbiological environmental
monitoring is carried out regularly for assessing the cleaning and hygiene measures.
4.2.3
GMP-critical computer systems
The complete materials management and the order processing are generally implemented with the help of an
ERP system (GUS-OS ERP) (refer to 1.9.1). The access is regulated by means of passwords and user profiles.
Computers and microprocessors are used during manufacturing as well as packaging for process control and
monitoring.
When weighing, the weighed components are recorded by a log printer according to the quantities.
A paperless recorder is used during manufacturing for recording the process data. The measured data is saved
and evaluated using special software.
During the packaging, scales are used with printers and statistics programmes, which allow the fill quantity to
be checked in accordance with the pre-packaging ordinance and its proper documentation.
In the Quality Control laboratory, the computers are used as stand-alone solutions, mostly for controlling measuring devices and for evaluating the analysis results. The archiving of raw data is defined in a SOP. The
management of reference substances, chemicals, reagents and standard solutions is implemented using the
ERP system (OS laboratory).
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Documentation
The content of the GMP-compliant pharmaceutical documentation and the handling are described in different
SOPs, operating instructions and other documents depending on the department. The persons in-charge are
also mentioned in them and the log formats and archiving are defined as well. The documents will be prepared
and updated in the relevant department in each case. In case of updates, they will be replaced with the new
version, stamped as invalid and preserved. The copies will be destroyed.
The documents are hierarchically structured and range from the general, rather descriptive document to general and more specific specifications right up the documents with the logging function (refer to figure).
The documentation system predominantly exists in hardcopy form and is thus also mainly manual.
SMF
SOPs, VMP
Description and specification
Specifications for general and comprehensive processes
Testing instructions
Manufacturing and operating instructions, maintenance instructions,
IPK instructions
Specifications for specific processes
other operating instructions, specifications,
plans, lists
Forms, logs, reports
Documents for documenting activities as well as results
The documents are archived in the rooms in accordance with a valid manufacturing authorisation. No documents are archived outside the plant.
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Production
6.1
Type of products
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At L-A-W Services GmbH, Leipziger Arzneimittelwerk, the manufacturing of liquid and semi-solid as well as
the packaging of liquid, semi-solid and solid pharmaceutical dosage forms is carried out on a contract basis.
These products mainly concern pharmaceuticals for human use.
The preparations are non-sterile semi-solid and liquid preparations for oral and external use as well as solid
dosage forms for oral use. A detailed list of the preparations can be taken from the annexes 1 or 4 (closed
part).
The dosage forms of the manufactured investigational medicinal products are identical (also refer to annexe 1
closed part). Investigational medicinal products will be manufactured in the manufacturing rooms. During the
manufacturing, the employees will be assisted by the specially trained employees from galenics.
The plant manufactures products, which contain the following substances, which are allocated to the toxic and
hazardous categories:

Substances with hormonal effect

Teratogenic substances

Ectoparasites

Other potentially hazardous substances.
The following categories of toxic and hazardous substances are not used during manufacturing:

beta-lactam antibiotics

Cephalosporins

Sex hormones

Prostaglandins / cytokines

Cytostatic agents

Immunosuppresive agents

Prions

Genotoxic agents

Radioactive substances.
For reasons of personal as well as product protection, active pharmaceutical ingredients and other substances
with hazard potential are weighed at a different safety weighing workstation and suspended/dissolved in an
excipient. Likewise, the blistering of solid forms with less therapeutic index and hazard potential will be carried
out on separately enclosed blister lines with special safety precautions (ventilation system, pressure zone
concept, lock concept, extractions). In the containments, the blistering of solids can be carried out in the form
of unprotected formulations with APIs having a sufficient therapeutic index as well as in the form of protected
formulations with APIs having a less therapeutic index. One of the containments, owing to its design, also
allows the blistering of solids, which are available as unprotected formulations with APIs having a less therapeutic index (lowest therapeutic dosage ≤ 10 mg).
The most varied work equipment and system parts are used only in a product-specific or product group-specific
manner for preventing cross-contaminations, such as weighing equipment, tubes, etc.
If the manufacturing systems/ rooms used are not used dedicatedly, this will be approveded risk- based. The
following measures are implemented among others for preventing cross-contamination or intermixing or incorrect labelling:
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Marking, cleaning validation, line clearance, corresponding clothing regulations, hygiene regulations and
codes of conduct for personnel, limiting and checking access regulations as well as suitable clean room classes, hygiene concepts and air and pressure zone concepts in the manufacturing departments bulk manufacturing and packaging
Process-analytical technologies are not used.
6.2
Process validation
The execution of process validations is defined in the validation master plan.
Pharmaceuticals to be manufactured for the first time will be prospectively or concurrently validated on the
basis of three validation batches. The validation plan contains all the measures, such as additional in-process
checks or the like, which have turned out to be necessary owing to the risk analysis, with their specifications.
The documentation of the process validation consists of the validation plan and the validation report. If faults
still need to be rectified, it is recorded in a nonconformity report.
The plan as well as the report will be generated by the persons carrying out the validation, checked in the
specialist departments and approved by the Head of Manufacturing. With the approval of the report, the validated process will also be approved simultaneously.
The following procedure is followed during the process validation:
 Description of the validation object
 Definition of the responsibilities and schedule
 Description of the manufacturing procedure with reference to approved instructions; justification of the
procedure during matrixing
 Description of the quality features of the end product
 Execution of the risk analysis taking into account the values influencing the process and the quality of
the product (raw materials, process equipment and its calibration and qualification status)
 Definition of the acceptance criteria for the process flow, the setting parameters of the equipment and
for tests
 Definition of the validation scope (in case of prospective or concurrent validation in general of three
batches)
 Creation of the sampling plan and inspection plan with the inspection methods
 Definition of the documentation and the test evaluation
 Data collection
 Generation of the report with evaluation of the data, if necessary assessment of deviations and faults
and definition of subsequent measures.
A revision is permissible in an exceptional case if the quality of the end product is not affected and the specifications are adhered to.
Decisions about any possible revisions (reworking, reprocessing) of a batch, for which the prerequisites for a
batch release do not exist, will be taken in a common agreement between the Head of Manufacturing, Head
of Quality Control, Qualified Person and the customer. The batch has to remain in the “Quarantine” status up
to this or any other decision.
A reworking / reprocessing of the manufactured products is permissible for L-A-W Services GmbH only after
a written approval from the customer and will be carried out in accordance with the instructions approved by
the contractor and customer.
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In case of a necessary reworking / reprocessing, both the parties agree upon measures with each other that
may be additionally necessary, such as

Scope of the analytical tests (additional IPK or release tests)

Specifications and scope of the documentation (SOPs, specifications, batch documentation, etc.)

Qualification & validation measures

Training of the employees

Stability tests.
The reworking/reprocessing process is described in detail in a manufacturing record and enclosed with the
batch documentation.
6.3
Material management and storage
Measures for working with raw materials, packaging material, bulk products and finished products,
including sampling, quarantine, release, blocks and storage
Manufacturing batch
Every batch of any delivered material receives an internal batch number, which will be allocated serially. The
internal batch number helps to ensure the retraceability of all the materials, i.e. every further inspection or use
of these materials will be controlled with these internal batch numbers.
The batch number of the manufacturer / supplier will be noted in the EDP system (ERP system) on the supply
notes with the pallets as well as on the inspection log so that it can be retraced to the manufacturer.
Sampling plans
The Quality Control is responsible for preparing and approving all the sampling plans.
The sampling of the delivered primary materials (raw materials, packaging materials, bulk products) is the
responsibility of the Head of Quality Control and will be carried out by trained personnel of the Manufacturing
/ Storage and Quality Control departments according to the sampling plans, which are available for all the
materials subject to mandatory testing.
The bulk products for testing will be sampled by employees of bulk manufacturing in accordance with the
corresponding sample plans. The employees were trained for this activity.
During the packaging, the shift in-charge will take samples for the microbiological testing, the testing of the
packaging and reference samples. Sampling plans are available for this too.
The sampling for the microbiological and particulate monitoring as well as for the monitoring of purified water
will be carried out by trained employees of the Quality Control department (employees of the microbiological
laboratory) or trained employees of the Manufacturing department. The sampling is specified / described in
the respective underlying instructions. For the compressed air monitoring, the sample is done in accordance
with the instructions by employees of the Manufacturing and Technology departments.
Status tracking
The status marking of the materials is carried out in the ERP system, whereby access options too are controlled, as well as by means of physical marking using coloured supply notes with the pallets or labels.
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Stock issue for manufacturing and packaging
Generally, only raw materials (active pharmaceutical ingredients, excipients), bulk products, intermediate products, semi-finished products and packaging materials, which have been approved by the Quality Control department, may be used for manufacturing and packaging.
The raw materials for a manufacturing order will be provided via a collective release order from the raw materials warehouse in accordance with the material number and internal batch number, checked and compiled on
pallets after weighing with respect to the orders.
The packaging materials will be transferred in an order-related manner via a collective release order from the
warehouse in the assembly area of the packaging to pallets.
The bulk products will be provided in an order-related manner via a collective release order from the corresponding warehouse in accordance with the material number and internal batch number and transferred to the
packaging area.
One pallet must not contain materials for multiple orders.
Checking the weighing
The raw materials will be weighed at the central weighing location of the Manufacturing department. Two
weighing labels will be printed out in each case. One weighing label remains on the weighed raw material and
the second will be on the manufacturing order. The accuracy according to type and quantity will be checked
by two employees and confirmed with initials on the manufacturing order.
The weighted sample of active pharmaceutical ingredients will be checked by the department head. The active
pharmaceutical ingredient container will generally be sealed.
Inspection methods
The identity and status will be checked by checking the name, material number, internal batch number and
release status before every relocation or consumption of a material. These checks will be conducted in accordance with the four-eye-principle.
Labelling and release of the materials required for manufacturing
All the pallets with raw materials (active pharmaceutical ingredients, additives), bulk products, semi-finished
products and packaging materials receive a supply note with the pallets (PBS) containing at least the following
information: status, material number, name, quantity, internal batch number.
All the incoming or manufactured products are automatically put into the quarantine status.
After Quality Control has tested and released the products, they will be physically marked and their status will
be changed in the ERP system.
The authorised persons for the release of the different materials are specified in SOPs.
Checking the bulk products manufacturing
Checking and recording the most important parameters
Detailed manufacturing instructions are available for every product, which simultaneously serve as a manufacturing record.
The integral parts of the manufacturing instructions are specifications for structuring the product and a detailed
description of the manufacturing procedure including process data and in-process checks.
The parameters of a manufacturing process are checked accurately and the actual process data is transferred
to the manufacturing record in writing. Product temperature, internal pressure as well as speeds of the mixer
and the homogeniser will be recorded during the manufacturing using a LOGOSCREEN paperless recorder,
then saved on a disk, evaluated using the PC and printed out as diagrams.
Manufacturing instructions/record, weight printouts for the raw materials and bulk products as well as the results calculations are integral parts of the manufacturing documentation. The process data logs are archived
with the Manufacturing group head.
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IPC and its recording
The in-process controls to be conducted are also an integral part of the manufacturing instructions. The data
will be transferred to the manufacturing record in writing and signed.
The bulk product will be weighed and the results will be calculated.
Compliance with the registration documents
The respective customer is responsible for checking and ensuring the conformity with the registration documents in case of pharmaceuticals or the compliance with the product dossier and other registration documents
for other product classes with the manufacturing instructions.
Checking the packaging
Packaging instructions and records are available for the packaging.
Release of the bulk products, semi-finished products and packaging materials
Generally, only bulk products, intermediate products, semi-finished products and packaging materials, which
have been approved by the Quality Control department, may be used for packaging. The responsibility for the
release of different materials is defined in SOPs.
The status of the materials is changed in the ERP system as well as physically on the materials.
Line clearance, confirmation of the identity of packaging materials and bulk as well as line release
Before the packaging is started, a check is conducted to ensure that the packaging line and the surroundings
are completely tidy and devoid of contaminants. All the materials and the line will be checked by the packaging
employees and these processes will be documented in the packaging record.
The packaging line will be provided with a label, which contains the product name, the batch description and
the expiry date of the product to be packed. After checking and setting up the scales and the monitoring equipment (code reader, Lumat) and checking the labelling on the packaging container sample, the line is released
for packaging.
When delivering the materials to the line, the shift in-charge checks the identity of the bulk products and the
packaging containers with the help of the material numbers, the internal batch numbers and for printed packaging containers, additionally with the help of version numbers and documents the correctness in the packaging log.
IPC and its recording
As in-process-controls during the packaging, fill quantity checks are continuously conducted in accordance
with the Fertigpackungsverordnung (regulation for final packages), at least hourly checks of the labels as well
as checks for the completeness of the packaging. The stated in-process controls are an integral part of the
packaging documentation.
The packaging lines have modern code readers for tubes, labels, package inserts and folded boxes. The
correct functioning of the code readers is checked and documented before the order is started and tested
repeatedly during the order processing. A luminescence reader checks the presence of the package inserts in
the folded boxes. The function of this device too is tested repeatedly during the order processing.
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Compliance with the registration documents
The respective customer is responsible for checking and ensuring the conformity with the registration documents in case of pharmaceuticals or the compliance with the product dossier and other registration documents
for other product classes with the packaging instructions.
Working with rejected materials and products
Working with rejected materials is defined in a SOP.
Rejected materials and products are provided with a red label “GESPERRT” or a red supply note with the
pallets and preserved in spatially separated stores for rejected material until they are destroyed or returned.
In the ERP system, rejected materials are provided with the “04” status (rejected).
Materials, which need to be disposed, are supplied to the assembly area for disposal. From there, these materials are handed over to a waste management company. This process is properly documented using dock
receipts or supply notes and the proof of disposal or collective disposal.
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Quality control (QC)
The processes for quality control are regulated in the form of SOPs, operating instructions, testing instructions
(consisting of components such as specifications, test methods, sampling plans, inspection plans). Documents
containing instructions are subject to an approval cycle and distribution. Specifications are generally prepared
based on the registration documents or other specifications of the customer. Specifications are approved by
the Head of QC. The specifications for bulk, semi-finished and finished products are approved by the Qualified
Person and the customer. The responsibilities and authorities for the release or rejection of the individual
intermediate levels and finished products are defined in SOPs.
All the relevant raw materials, packaging materials, intermediate products, bulk products and finished products
are tested analytically. The findings of release tests are included in the respective batch documentation e.g. in
the form of analysis reports or analysis certificates.
In particular,
physicochemical and organoleptic parameters
chemical parameters (identity, impurities, content of effective ingredients) as well as
microbiological purity (in each (partial) filling of manufacturing batches and microbiologically sensitive
bulk products)
are tested on the basis of approved specifications and the requirements of the European Pharmacopoeia.
The analyses are carried out by using qualified equipment, for which the operation, cleaning, maintenance,
function check and calibration is defined in device-specific SOPs or operating instructions.
The following analysis procedures are used among others: HPLC, GC, TLC, titration, IR and UV spectroscopy, testing of disintegration time and dissolution, density measurement, viscosity determination, pH-value
measurement.
In addition, the quality of the purified water as well as the microbiological and particulate environmental conditions in the manufacturing area is regularly monitored (surface tests, air determinations).
In addition to the routine analysis, stability studies (primary in accordance with ICH guidelines and on-going in
accordance with EU-GMP guidelines) are conducted for external customers. The following climatic conditions
are available for storing test samples:
25 °C / 60% relative humidity
The documentation system is regulated via SOP. Raw data is archived in hardcopy form and, if applicable,
electronically.
The procedures for working with reagents, standard solutions and reference substances are defined in SOPs.
Results out-of-specification (OOS) will be analysed and evaluated in accordance with a procedure defined in
a SOP.
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8.
Distribution, complaints, product defects and recalls
8.1
Distribution (for the part in the field of responsibility of the manufacturer)
The finished product manufactured by L-A-W Services GmbH, Leipziger Arzneimittelwerk on a contract basis
will be directly delivered to the respective customer or to a recipient specified by it. The dispatch is carried out
on the basis of the concluded Quality Agreements within Germany and, in isolated cases, within the EU to
companies having their own manufacturing authorisation. The party responsible for the transport in accordance
with the Quality Agreement must ensure suitable environmental conditions during the transport and the compliance with the GDP requirements. L-A-W Services GmbH generally delivers ex works (Incoterms 2010) and
does not assume any responsibility for transporting the finished products / contractual products to be delivered.
Deviating regulations are possible in agreement with the customer.
Generally, the respective customer is responsible for the transport; the transport is carried out in accordance
with its requirements.
If, in isolated cases, the responsibility for the transport lies with L-A-W Services GmbH, Leipziger Arzneimittelwerk, a transport validation is taken out with regular monitoring of the transports by adhering to the GDP
requirements.
The
transport
company is
selected
carefully in
accordance
with
the
requirements.
The transport requirements are derived from the storage instructions.
The traceability of the pharmaceutical deliveries or contractual products is ensured using the ERP system. All
the deliveries will be documented with the batch description of the dispatched product.
That products get into an illegal supply chain is prevented by the supply practice:
The product manufactured on a contract basis will be exclusively and directly delivered to the customer or to
a recipient specified by it.
8.2
Complaints, product defects and recalls
The process of dealing with complaints is regulated in a SOP.
The Sales department is responsible for processing the commercial complaints.
Complaints about the pharmaceutical quality fall within the scope of responsibility of that manufacturer, where
the products are produced based on contract manufacturing. In case of subcontracting of manufacturing steps
to third parties, contract manufacturers and contract laboratories are involved in the processing. The Head of
Quality Assurance is responsible for the processing flow. The processing is done by including all the relevant
departments. The resulting decisions and initiated measures will be documented. After the inspection is complete, a report is sent to the customer, who has complained about the product.
The documentation of the complaints will be regularly checked for references with respect to special or recurring problems, which require special attention and additional measures in order to derive subsequent measures
if necessary.
The records about quality-relevant complaints will be maintained in the Quality Assurance department for at
least 10 years.
The customer is responsible for processing medically relevant complaints as well as notifications of unknown,
undesired or serious side effects and this is mandatorily the responsibility of the respective customer (pharmacovigilance).
In case of product recalls, the Qualified Person who released the product will be informed by the relevant
customer; the recall of finished medicinal products will be noted in the batch register by the Qualified Person.
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Self-inspection
Self-inspections will be conducted in all the departments of L-A-W Services GmbH, Leipziger Arzneimittelwerk
for checking the functionality of the quality assurance system as well as for checking that the pharmaceutical
products are being manufactured, tested, stored and dispatched properly.
The execution of the self-inspections is defined in a SOP. The self-inspection program can be adapted in
accordance with the updated requirements during the year.
At the start of every year, a self-inspection plan will be prepared, which will be approved by the Head of Quality
Assurance and the Managing Director.
The frequency of the self-inspections in the departments is ascertained in a risk-based manner. A self-inspection is conducted at least once a year in the GMP areas of Manufacturing, Quality Control and Quality Assurance.
When planning the deadlines and contents of the self-inspections, the results of previous external and internal
audits, deviations, results of the data analyses, PQRs and complaints will also be considered among other
things.
The preparation and post-processing of the self-inspection will be done in agreement with the Qualified Person.
Generally, self-inspections are conducted by an inspection team, which consists of at least an internally approved inspector and another person. Both must not have any responsibility for the department being inspected
(the inspected issue). It is possible to also include outsiders in the inspection team.
A cover sheet for the audit report will be prepared as proof of the self-inspection; this cover sheet will contain
the date of the execution, the audited department as well as the participants.
An internal audit report will be generated as a result of the self-inspection, which will be evaluated by the
auditors together with the person in-charge of the audited department.
The audit report contains an action plan, in which the measures required for rectifying the ascertained faults
will be specified along with the responsibilities and deadlines. The measures receive a CAPA number and will
be included in the CAPA list.
The implementation of the defined measures will be monitored by QA within the scope of the CAPA system.

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