Southern African Regional and International Symposium
SARI 2014
CSIR International convention Centre, Brummeria, Pretoria
11-13 March 2014
QUALITY OF ACTIVE PHARMACEUTICAL INGREDIENTS (APIs)
Joey Gouws
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Content
• Introduction
• What is an API
• GMP for API sites
• Conclusion
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Introduction
• Ingredients come around the world – A large number of medicines are imported from
other nations including India and China
– Generics have the same API as the innovator on which their chemical make –up is based, different inactives are used
– Inactives may have different impurities or contaminants depending on source and origin
• Quality depends on both Active and inactive ingredients
MCC: Definition of “API”
Active Pharmaceutical Ingredient (API)
A substance or compound that is intended to be used in the manufacture of a pharmaceutical product as a therapeutically active ingredient
(MCC P&A guideline)
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Definition of Intermediate
• “A material produced during API processing that undergoes further molecular change or purification before it becomes the API”
• “May or may not be isolated”
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Start of GMP requirements for API’s
• Quality (chemical and pharmaceutical Quality Assurance)
• Safety (in vitro and in-vivo pre-clinical studies)
• Efficacy (clinical studies in human subject)
• Multidisciplinary (general topics)
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Establishment: ICH : Technical Topics
What is ICH?
I nternational
C onference on
H armonisation
of Technical Requirements for the Registration
of Pharmaceuticals for Human Use
Establishment of ICH
• Regulatory agencies – EC/EMA - European Union
– MHLW/PMDA - Japan
– FDA - USA
• Trade associations – EFPIA - Europe
– JPMA - Japan
– PhRMA - US
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GMP Guideline: ICH Q7
• EU, US, Japan – Implemented as Note for guidance / Guidance for industry
• WHO has implemented ICH Q7 – Technical Report Series 957, Annex 2, 2010, 130-189.
• PIC/S has implemented ICH Q7 – GMP-Guide PE 009-9 (Part II) 1 Sept. 2009 : Note for guidance.
• International implementation of ICH Q7 – Many countries implemented ICH Q7 as is (e.g. Australia, Canada,
Switzerland) – Some countries reference to WHO or PIC/S requirements, if needed (e.g.
ASEAN and SFN, Brazil) – Some countries use the content (e.g. China: Annex 2 of GMP 2010.)
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Implemented world-wide
Where does API Process begin?
Earth
Fire Water
Wind
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Definition ‘API Starting Materials’: Company specific
• The company should designate and document the rationale for
the point at which production of the API begins. For synthetic
processes, this is known as the point at which “API Starting
Materials” are entered into the process. (1.3)
• From this point on appropriate GMP, as defined in the guidance,
should be applied to these intermediate and / or API
manufacturing steps. (1.3)
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Applying ICH Q7
Chemical Manufacturing
Introduction of
API Starting
Material
Production of
Intermediates
Isolation
&
Purification
Physical
Processing &
Packaging
Outside scope
Covered by ICH Q7
Production of
API Starting
Material
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Overview: GMP for APIs (ICH Q7)
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ICH Q7 along End-to-End Quality
API starting material
API Production (up stream)
API Purification (down stream)
API Distribution
Manufacturing Distribution API Starting Material
Tabel of Content
API Production & Purification (up stream / down stream)
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GMP Controls in API Manufacturing
Apply GMP controls beginning with the use of
API starting materials
Controls increase as process proceeds to final isolation and purification steps
Degree of control depends on process and manufacturing
stage
‘API starting material’ is defined in the filing as
per ICH Q11
‘Starting material’ (for Drug products)
Section 1: Introduction
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Quality Management Chapter 2
• Quality and Production Complementary Responsibilities – Some similarities, but intentional differences
Approving all specifications and master production instructions
Preparing, reviewing, approving instructions for the production of APIs and intermediates
Quality Unit Production
Section 2:
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Quality Management...cont
• Quality and Production Complementary Responsibilities
Making sure that effective systems are used for maintaining and calibrating critical equipment
Making sure that the necessary calibrations, qualification, validations are performed and records are kept
Quality Unit Production
Reviewing completed manufacturing records for critical process steps before release of API for distribution
Reviewing all production records and ensuring these are completed and signed
Section
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Personnel Chapter 3
• Requirements for tasks are described
• Every person has appropriate qualification
• Periodic training to be performed and assessed
• Hygiene should be established and maintained
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Building and facilities Chapter 4
• Designed to accommodate different processes and to protect operators
– Controls are most critical when API systems are open
• Focus on utilities that could impact quality
– Product contact: Steam, gases, compressed air, HVAC
• Prevent cross-contamination from personnel & materials
– Appropriate containment
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Building and facilities...cont
• Difference in design, features, and level of control necessary for API facilities compared to the manufacture of final dosage forms – Final isolation and filling of APIs are likely to be
more similar to those for handling starting materials in drug product facilities
• Controls for APIs that could be sensitizing, toxic, or require microbial control will be different
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Building and facilities...cont
• Water – Process water meets WHO guidelines for potable/drinking water quality
(4.31) - at minimum
– Sampling is usually done at the point of use
– A rational of using different water quality at different manufacturing steps shall be justified
– Typically at the final processing step of the API ‘purified water’ is used to ensure consistency of quality
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Process Equipment and cleaning validation: Chapter 5
• Appropriate design and maintenance of equipment – Designed to avoid contamination and cross-
contamination
– Impact on GMP controls of computerised systems should be understood and validated
– Calibration schedules and procedures should be justified on a science based approach
• Cleaning should be managed as the process – Failures should be recorded and investigated
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Process Equipment and cleaning validation...cont
• Cleaning procedures should normally be validated (12.70)
– For complex API plants validating cleaning processes might not be possible to the extend that there is absolute confidence in the cleaning method without performing verification at each change over.
– For all changeovers cleaning according to appropriate standards should be conducted.
– Cleaning need to be performed and verified to appropriate standards
– Evidence is needed that residues will be removed by the process to a level they typically found at end of cleaning
– Other example might be two consecutive steps of the same syntheses or dedicated versus multi purpose equipment
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Documentation and Records Chapter 6
• Documents need to be managed: issued, distributed, when and where used, reviewed, archived etc.
• Documentation system needs to be described and maintained appropriately – Equipment, Cleaning & Use Record – Records of Materials – Master production instructions, batch record and
batch record review – Laboratory Control Records
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Materials management Chapter 7
• Be clear on the categorisation of the material – Material, raw material, reagent, solvent, process aid, packaging
material, API starting material
• General needs – Specification
– Evaluating, approval and change control of suppliers of critical materials
– Receipt, quarantine and re-use procedures
– Sampling and Testing (ID test at least)
• Storage of Materials – Prevent degradation, contamination & cross-contamination
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Materials management...cont
• Written Procedures (7.10)
– A list of approved suppliers is required (7.12)
– ICH Q11 defines what to file as ‘API staring material’. This is the starting point for GMP according ICH Q7 at least
– Some materials can have different classes depending on the use e.g. a solvent can also be an API-starting material (e.g. Ethylene dichloride, Acetonitrile).
– The ‘worst case’ have to be applied.
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Materials management...cont
• Suppliers approved by the quality unit (7.12)
– Approval by the purchasing department is not regarded adequate
• System for evaluating suppliers of critical materials (7.11)
– API starting material, building blocks and solvencies used in the final stage at leased are regarded as ‘critical material ‘
– Also not mandatory : this evaluation should usually include and be based on audits by or on behalf of the company
– This right should be in the contract
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Materials management...cont
• Receipt & Quarantine.... assurance of no cross-contamination from tanker (7.22)
– Using certificates of cleaning should be preferably supported by an audit of the transport company or an alternative type of assessment giving adequate confidence of the validity of the certificate
• System to identify status of each batch (7.24)
– A system should be in place to ensure the status of the different containers of each batch is clear. This may depend on how the batch is used in productions
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Materials management...cont
• Storage of Material (7.40)
– Small qualities (e.g. tailings) are often stored separately. The controlling should be equivalent to the main batch.
– Storage facilities should be temperature and humidity mapped in worst case seasonal conditions
– Normally first expiry first out (FEFO)
– Assessment of the suitability of the labels to remain legible over time (e.g. influence of sunlight, rain)
– Containers with out side storage should be sealed
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Production and In process Controls: Chapter 8
• All controls should be based on clear understanding of process capability and process requirements
• There should be a strong scientific bases for all decisions and controls
• Adequate sampling plans and procedures
• No blending of batches having an OoS
• Understand and manage risks to minimize contamination and cross-contamination
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Production and In process controls...cont
• Goal: Avoid contamination and cross-contamination
• Weighing and measuring devices …for intended use (8.10)
– Depending on process requirements
• Materials … stored in suitable containers (8.11)
– Potential issues of mixing different materials, mislabeling, storage conditions
• Critical weighing ..should be witnessed (8.12)
– Witness: In law means to have been present and observed; Within ICH: It is meant to be equivalent to supervision AND peers could also fulfil the role
– Two independent checks: In case of a electronic print out you also need a check by an operator of the print out to be valid
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Production and In process controls...cont
• Other critical activities should be witnessed or subjected to an equivalent control (8.13)
– Equivalent control means confirmation by a second independent means, e.g. printout from electronic or mechanical source.
– Critical process parameters (CPP) have to be confirmed frequently. Documented evidence to demonstrate full control in line with the process requirements
• Deviations from expected ranges should be investigated for critical steps (8.14)
– It is expected that manufactures have an understanding of the process capabilities / requirements and of the process critical steps and ranges
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Production and In process controls...cont
• Blending (8.42) – These should be on a routine planned and documented process – There is no restriction on number of batches to be used – Consider cases where specifications are met but the impurity profile is
not the same – Consider stability studies using blended batches as representative of
materials supplied to the customers – How to know that blending does not effects stability without conduction
a stability program (more likely physical properties effected e.g. particle size)?
– Expiry or retest date of blended batch should be based on the manufacturing date of the oldest tailings or batch in the blend (8.47) - This is a very clear statement which is often misunderstood
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Production and In process controls...cont
• Precautions to avoid contamination should be taken when APIs are handled after purification (8.52)
– In general contamination should be prevented at all stages of manufacturing
– There is no more processing to remove contamination
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Packaging and Labelling Chapter 9
• There is a high risk if these processes are not under control
– There can be misconceptions on the use of materials
– Mix up of material with different customer specification
– Repackaging, Relabeling operations
• The activity should also be under the scrutiny of the quality unit
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Packaging and Labelling...cont
• The primary packaging material should be handled in a way that it will not compromise the quality of the product
• Also when containers are re-used for the same products (dedicated containers) a cleaning procedure should be agreed between the parties
• Cleaning records must be kept
• Excess batch labels / printing destroyed (9.32) Purpose: make sure that the excess labels are not misused
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Packaging and Labelling...cont
• Facilities inspected immediately before use (9.44)
– Called ‘line clearance’ in drug product manufacturing
• Intermediate / API transported outside of manufacturer control (9.46)
– The standard of security seals should be tamper evident and have an identifier (e.g. name / logo of the company)
– The customer should be aware of the type of seal used
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Storage and distribution Chapter 10
• Awareness of the storage and transport conditions over the supply chain
• Storage and transport under appropriate conditions and oversight
• When? Where?....are the material?
• Distribution of APIs and Intermediates requires approval by the Quality Unit
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Storage and distribution...cont • Transport / Distribution
– There are local regulatory requirements not allowing shipment under quarantine in some countries
– Manufactures should understand the challenges caused by the shipping route e.g. - Exposure to direct sunlight while awaiting air/sea fleet - Container at the top of container ship - Airplane: can get to -50oC if not pressurized - Foil used to protect against rain
– Labels should ideally state the maximum and minimum of
temperature for storage / transport
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Laboratory Controls Chapter 11
• Expectation not different from expectations for laboratories that test medicinal products (e.g. Standards, OoS)
• Management of reference standards
• Clarity and integrity of raw data
• Methods validated or fit for purpose
• Expiry & Retest Dating based on data from real time stability studies
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Laboratory Controls...cont
• Testing APIs and Intermediates – May be appropriate not to do complete testing after each step e.g. after
blending, milling for parameters which had been demonstrated that they would not be affected
• Impurity profile – Biotech APIs are covered in ICH Q6B
– Not always relevant for API manufacturing which do not include chemical synthesis (e.g. from herbal or animal tissue source)
• Suitability of analytical methods – Verified under actual conditions of use and documented (12.80)… where
a Pharmacopeial method is used
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Laboratory Controls...cont
• Certificate of Analysis (CoA) • Reflect the actual manufacturing site address
• Transcriptions should be clearly identified as such but not replacing the original
– Label (11.41)
• The date of manufacturing is typically expected
• Expiry date on the CoA & label
• Retest date on the CoA and/or label
– Each test with acceptance limits & numerical results ...rather than ‘conform with specification’ (exception e.g. IR)
• The results reports should be inline with analytical method validation reporting e.g. ‘less than limit of detection’
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Process validation Chapter 12
• Goal: Generate evidence of consistency
• Risk and science based approach – An understanding of processing go a long way towards
determining what aspects of an operation are critical
• Validation Master Plan – The key elements of a qualification and validation
program of a company should be clearly defined and documented
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Process validation...cont
• Critical steps need to be clarified
• Not validating a step does not mean that there is no control
• Traditional approach: A Manufacturing processes: Repeatability;
• Enhanced approach: A Manufacturing processes: Capable and Robust: Over time the enhanced approach should be the norm and applied also for existing processes – For continuous process verification (CPV) all batches are in the scope
– Using the enhanced CPV approach the requirements for periodic review is automatically fulfilled
• Retrospective validation: Historical concept: companies no longer make use of this approach as their sole evidence of validation and are moving towards CPV
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Change control Chapter 13
• ICH Q7 describe the change control activities linked to GMP and the change management element of the Quality Management System (see ICH Q10)
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Change control...cont
• Change Control includes …(13.11)
– Anything that has potential impact on the API / intermediate quality or the regulatory dossier need to follow a change control procedure
– Any maintenance change (incl. exact replacements = ‘like for like’ changes) needs to be assessed and documented in the engineering records at least.
– It is practice to allow like for like changes without going through the full change control. This procedure must be approved by QA.
– It is good practice to consider failure modes that results from the covered change
– Consider proposed cumulative changes and previously initiated changes as these may have a greater impact than a single minor change
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Change control...cont
• Customers should be notified of changes from established production and process control procedures that can impact the quality of the API (according 13.17)
– The customer is responsible for defining what changes they expect to be informed of and this should be defined in a procedure e.g. in a quality / technical type agreement
– In some cases this may be conducted by an agent, distributer or repacker
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Rejection and reuse of materials Chapter 14
• Reprocessing – Generally an acceptable way – If used routinely it should be part of the established process – Normally covered by the existing registration
• Reworking – Alternative way of treating material which may not initially have met the
specification – Only be used after an extensive evaluation – May need additional approval by the authorities
• Recovery – Limited to specific and predetermined situations (e.g. solvents or second
crops of crystals) – For the API itself approval of the authorities is required
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Rejection and reuse of materials...cont
• Returns
– It needs to be understood what really happened outside of the companies control
– Consider if the original seal is still there
– Consider to make a full testing of a returned batch
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Complaints and Recalls Chapter 15
• Investigations are recorded
• Corrective actions and preventive actions should be implemented (effective CAPA system)
• The system must be confirmed to be efficient and meet timelines
• Authorities are informed appropriately by the marketing authorisation holder (following local requirements)
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Contract Manufacturer Chapter 16
• On behalf of the original manufacturer contract manufacturers comply with GMPs as defined in Q7
• Changes must be under control by the contract giver and approved prior to implementation
• An appropriate knowledge exchange must be implemented
• Manufacturing contractors should be on the registration dossier; manufacturing authorization may be required according to local requirements
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Contract Manufacturer...cont
• Agents, Brokers, Traders, Distributors,
Repackers and Relabellers (ABTDRR) have to
follow Q7 requirements, if any of the
respective operations of Q7 are performed
• Provide the name of the original manufacturer
and batch number to customer and regulatory
authorities according to the local procedures
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Contract Manufacturer...cont
• Supply Chain tractability (17.2)
– This is already a requirement in ICH Q7
– Today traceability may be referenced as ‘pedigree’
– ABTDRR must not withhold the identity of the original manufacturing sites (including the original CoA, see 11.44)
– ABDTRR need to have appropriate level of technical skills for the type of activates undertaken (3.10)
• Repacaging /Relebelling (17.3)
– Traceability has to be maintained between original and repack material (e.g. by appropriate identity testing)
– There need to be appropriate steps in place to maintain the integrity of the repackaging operations
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Contract Manufacturer...cont
• Stability(17.5)
– Different types of container = different container closure system and/or different types of material (same type of containers e.g. other color, other size)
– Stability studies under these condition have to maintain the original retest date
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API for use in Clinical trials (IMP) Chapter 19
• GMPs for APIs on investigational medicinal products need to be risk based
• Unique circumstances:
– Processes and controls change during development
– Few batches may be produced identically
– Batches are frequently produced in small non-commercial scale equipment
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API for use in Clinical trials (IMP)...cont
• In General
– Control and use of clinical trials / investigational medicinal products (IMP) should be proportionate to the risk of patient safety
– Investigations into yield variations are not expected
– Changes in production, specifications, test procedures should be adequately recorded (19.70). The level of effort and formality of change controls are not equivalent to those expected for commercial material (Section 13)
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API for use in Clinical trials (IMP)...cont
• Documentation – Records should be available at the place of manufacturing e.g. for
inspections (i.e. retrievable)
– Regional requirement for record keeping have to be considered and might be longer than for commercial
• Laboratory Control – Stability studies not normally performed for development batches
– Stability studies for registration often conducted simultaneously with development
– It may be necessary to consider testing prior use for formulation if there is no retest / expiry date specified
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Conclusion
• API manufacturing is unique
• Imperative to remove your “Dosage” hat and put your “API” hat when conducting inspections or audits of active pharmaceutical ingredient manufacturers.
• “Dosage hat ” may let you focus on issues that have little or minimal impact on the process or the quality of the final API.
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When inspecting or auditing API Manufacturers
Please wear your API hat!
APIs
DOSAGE
DEVICES
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Acknowledgement
• This presentation represents an update of the 2001/2002 version by ICH Q7 EWG members organised in a joint initiative between PDA and PIC/S developed in 2012with input form members of the PIC/S Q7
expert cycle and other PDA volunteers
• ICH Q7
• PIC/S GMP Guideline, Annex II
