API process

Question 1

What are possible contaminants of API

Answer 1

Physical:
Equipment - Gaskets, Nuts / Bolts, Glass, Metal Swarf.
People - clothing, hair, tools, etc
Materials - raw materials, cleaning solutions
Environment - Building fabric, HVAC, Pest control
Chemical: ICHQ3A Related Substances, ICHQ3A Materials, GMP, ICHQ3C Solvents, ICH Q3D Metals, ICH M7 Nitrosamines
Micro: Water, starting materials from natural origins - micro contamination largely destroyed / removed due to processing conditions pH, Temp, pressure etc

Question 2

What are the main risk factors when assessing the risk of nitrosamine contamination in medicinal products?

Answer 2

Synthesis routes / Steps in the Manufacture (nitrosating agents and a 2ndary or 3ary amine)

Use of contaminated recovered Solvents

Starting Materials, intermediates, reagents, solvents (e.g. DMF DMAc (dimethylacetamide), NMP)

Catalysts (with an amine functionality)

Water disinfected (chlorination, chloro-amination) in the presence of 2dary or 3ary amines

Impurities (amine, e,g, quats, from quat anion exchange resins), degradation products (storage/manufacturing) by oxidation of hydrazines, hydrazides and hydrazones

Packaging Materials (e.g. lidding foil containing nitrocellulose)

Need to determine specific potential levels of Nitrosamine contamination
If beyond certain levels – action will be required to reduce these levels within the manufacturing processes / synthesis routes.

Question 3

What are the deadlines for submitting nitrosamine risk assessment outcomes to the EMA?

Answer 3

Step 1 (risk evaluation)
31 March 2021 for chemical medicines;
1 July 2021 for biological medicines.
Step 2: nitrosamine confirmatory testing
26 September 2022 for chemically synthesised medicines
1 July 2023 for biological medicines
Step 3: risk mitigating, submission of variation
1 October 2023 for chemical medicinal products
1 July 2023 for biological medicines

Question 4

API retest dates?

Answer 4

Usually 3 year registered retest date. Use stability data to support - use after this date requires retest before use

Question 5

How are APIs regulated?

Answer 5

SI 2012:1916, EU GMP Part 2, FMD 2011/62

Question 6

How would you progress a request from the purchasing department to change a raw material used in the production of an API?

Answer 6

I would raise a change control and walk through the process: Impact assess, high level plan, actions required, change implementation, effectiveness check

Question 7

What guidance could help you in auditing an API Site?

Answer 7

Part II/Q7? Was looking for PIC/S guide

Question 8

For an API process define re-processing and re-working?

Answer 8

Reprocessing is for confirming and non-conforming batches and utilitises an already established process. Reworking is for non-confirming only and may include a step that is different from the normal process

Question 9

What is required as a minimum to re-work?

Answer 9

The rework must be risk assessment, follow a defined protocol and be pre-approved by the quality department

Question 10

Describe the impurities that can be found during chemical API synthesis and the methods of purification used?

Answer 10

Impurities may come from environmental, materials, chemical, biological or physical challenges.
They include process - residual solvents, catalysts, heavy metals, filter aids etc. People - hair, clothing, paper, tools, microorganisms. Materials - raw materials, nitrosamines, water, micro. Equipment - valves, gaskets, glass fragments or metal swarf etc
Facility - building fabric, cleaning agents, HVAC

Question 11

Name some API purification techniques

Answer 11

Purification includes distillation, chromatography, centrifugation, extractions, evaporation

Question 12

API manufacture – do they legally have to comply with GMP? When would you want GMP to start in process?

Answer 12

API has a sliding scale of GMP, for chemical API it starts with the introduction of the registered starting material. For Biotech it’s the maintenance of the working cell bank. Should follow EUGMP Part 2 and ICH Q7 - GMP for API

Question 13

For 8 stage chemical synthesis where would you want to see GMP start? What conditions would you want to see at final crystallisation stage (e.g. what would the operators be wearing?).

Answer 13

Introduction of the registered starting material. Final crystallisation phase is the critical stage of the process, although the manufacture of API should be as far as possible in a closed system appropriate protective clothing, such as head, face, hand, and arm coverings, should be worn when necessary, to protect intermediates and APIs from contamination.

Question 14

What air quality/ grade of filters should be used for final stage API synthesis?

Answer 14

Adequate ventilation, air filtration and exhaust systems should be provided, where appropriate. These systems should be designed and constructed to minimise risks of contamination and cross-contamination and should include equipment for control of air pressure, microorganisms (if appropriate), dust, humidity, and temperature, as appropriate to the stage of manufacture. Particular attention should be given to areas where APIs are exposed to the environment. If air is recirculated to production areas, appropriate measures should be taken to control risks of contamination and cross-contamination.

Question 15

Traceability, control over number of times recycled, recycled for the same product, QC test impurity profile

Answer 15

Traceability, control over number of times recycled, recycled for the same product, QC test impurity profile

Question 16

Bulk active manufacturer- A new manufacturing method is introduced for a bulk active material. As a user of this bulk active in your Pharma products, what licence changes do you make?

Answer 16

You will need to raise a change control to assess. This would include a regulatory and toxicologist assessment. Updates would be required for the registered starting material and submissions would need to be made to all countries - this could be phased and managed with flavour management. Validation would need to take place to confirm the active is comparable both chemically and microbiologically (although maybe dependent on its use). Will any new methods need to be validated? A risk assesses number of validation batches will need to be manufactured with the new active and we will also need to lay down stability studies.

Question 17

What is a polymorph and what effect can it have on a product?

Answer 17

A material that takes on various forms. It is developed at the crystallisation step. Different polymorphs may act differently within the body and have a huge impact on how a drug behaves - impacts ADME

Question 18

An audit is required to be performed on a critical API supplier
Does the QP have to do this audit? If it can be delegated, who can it be delegated
to? Yes it can be delegated, the auditor must be independent and have the correct qualifications/training.

Answer 18

Yes it can be delegated, the auditor must be independent and have the correct qualifications/training.

Question 19

What are the key things that you would focus on during an API audit?

Answer 19

Refer to PICs Aide Memoire
PQS
Inspection History
Dedicate or Multi-Purpose Facility – determine if any highly toxic or potent API’s
Supplier Evaluation
API Manufacture / Testing / Specifications
Material and Personnel Flow
Blending of batches / material
Solvent Recovery
Rework and reprocessing

Question 20

As part of the investigation it comes to light that your API manufacturer accidentally discharged recovered solvent from a different API manufacturing process into the vessel containing the solvent for purification of your API. They calculated the potential carry over and did not perceive any issues, so they did not tell you, it has since been identified that there were errors in the calculation
What do you do now?

Answer 20

Raise Deviation
Place Batch of API on hold
Determine if any of this Batch has been used in your Drug Product – if so put on hold
What was the different API?
What was the error in the calculation?
ICH Q3, - Did the API pass related substance testing? Any impurities ?
ICH Q7 – not good practice to use residual solvents from different API’s , Recovery (e.g. from mother liquor or filtrates) of reactants, intermediates, or the API is considered acceptable, provided that approved procedures exist for the recovery and the recovered materials meet specifications suitable for their intended use.
ICH M7 – risk of Nitrosamines ?

Question 21

What are your concerns about reusing a recovered solvent concern

Answer 21

Recovered solvent concern
Volatile API - traces of API remain in solvent which will carry over into next product
Test recovered acetone of residue of previous product - sensitivity of method / what sampling plan? Would this pick up any carryover
Accumulated impurities from the API
How stored, under what humidity, how quickly used?
Polymorphic concerns on long term stability - test for degradation products and polymorphism
Impact on particle size, flow rate, bioavailability - how many batches scoped
Registration allow?
How many reuse?
Need to understand the recovery stream - analytical methods only pick up what looking for
Recovered process under GMP
Detailed registered spec
Reuse in same product only
Market specific requirements
Nitrosamine concern

Question 22

Change to API crystallisation step - You manufacture ibuprofen tablets. Your API supplier informs you that they have changed the final recrystallisation step from methanol to toluene. How do you manage the introduction of this change?

Answer 22

Raise Change Control
Assess the impact of change
Understand the differences in the final API specification
Update to Nitrosamine Risk Assessment
Polymorphic form
Impurity Profile
CEP Update – changes MA
Process Validation
Stability Requirements
Changes to Particle size – comparative studies

Question 23

Tell me about nitrosamines

Answer 23

EMA, HMA and CMDh guidance published 22 February 2021
An ‘acceptable intake’ (AI) limit should be calculated for individual N-nitrosamines
* Based on the ICH M7(R1) principles for “cohort of concern” substances
* AI limit corresponding to a theoretical excess cancer risk of <1 in 100,000
* Considering a lifetime daily exposure

Mechanisms provided for calculating limits where:
*More than one nitrosamine is present and
* For instances where no limit has yet been set for a particular nitrosamine

3-step process required by the EMA/CHMP guidance of September
2019
Step 1 is a risk assessment. If this identifies a potential risk for
nitrosamine contamination of marketed products move to step 2
Step 2 requires confirmatory testing
* Immediate reporting of any nitrosamine detected
* Four possible scenarios (a, b, c and d) depending on the levels of nitrosamine(s) found and the applicable acceptable intake (AI) with the appropriate courses of action for each

The EMA Q&A on Nitrosamines was revised 7 times during 2022
Main issues are:
* Initial nitrosamines were contaminants
* Recently identified nitrosamines are related to the API itself
* If API contains a secondary amine group even a tiny amount of nitrite in the formulation can
lead to nitrosamine formation during shelf-life
* The toxicity of the API related nitrosamines is not known
* Cannot set acceptable intake (AI) limits
* Regulators are being super cautious
* Could lead to whole classes of medicines being withdrawn; e.g. beta-blockers

On 26 July 2022 Concept Paper proposing revision published
* Comments due by 31 October 2022

Changes proposed are:
* Guidance on appropriate process development in order to mitigate the potential presence of N-nitrosamines or other ‘cohort of concern’ (CoC) compounds
* The selected manufacturing process should be justified accordingly
* Guidance on the need to provide clear information on all the materials used in the process
Changes proposed contd.:
* Guidance on the required discussion regarding presence or formation of N-nitrosamines or other CoC compounds as well as of other potent toxins
* Clarify the new systematic approach suggested by ICH M7 on mutagenic impurities
* Guidance on the use of recycled materials
* Guidance on specific control options for N-nitrosamines or other CoC compounds as well as for other potent toxins, including possible control points and acceptance criteria
* Guidance on the need to consider formation of N-nitrosamines or other CoC compounds as well as of other potent toxins during storage

follows:
* Use of sodium nitrite or other nitrosating agents either:
 In the presence of secondary, tertiary amines or quaternary ammonium salts, or
 In combination with reagents, solvents and catalysts, which are susceptible to degradation to secondary or tertiary amines
* Use of contaminated raw materials, starting materials or intermediates
* Use of recovered materials, such as solvents, reagents or catalysts
* Use of contaminated starting materials and intermediates
* Cross-contamination from other processes
* Degradation processes of starting materials, intermediates and drug substances
* Use of certain packaging materials (it has been hypothesised that blister packing lidding foil
containing nitrocellulose printing primer may react with amines in printing ink to generate
nitrosamines, which would be transferred to the product under certain packaging process
conditions)

An ‘acceptable intake’ (AI) limit, based on the ICH M7(R1) principles for “cohort of concern”
substances, (AI limit corresponding to a theoretical excess cancer risk of <1 in 100,000) considering a lifetime daily exposure should be calculated for individual N-nitrosamines in human medicinal products. It also provides mechanisms for calculating limits where more than one nitrosamine is present and for instances where no limit has yet been set for a particular nitrosamine.

Question 24

API Purification methods

Answer 24

• Recrystallisation and filtration
• Decolourisation
• Precipitation/distillation/evaporation
• Solvent extraction
• Chromatography
• Resolution of optical isomers

Question 25

API Recrystallisation - Most common purification method for solids

Answer 25

• Crude product dissolved in suitable solvent…
• Solubility of impurities good
• Solubility of product increases with temp
• Temperature raised to boiling point
• Hot solution filtered and cooled
• Product crystallised
• Impurities remain in solvent
• Often combined with decolourisation, commonly using activated carbon (charcoal)
• Some loss inevitable, so often “second crop”

Question 26

API Isolation - separation of the desired material, usually solid, from the mother liquors

Answer 26

• Decantation of liquors
• Filtration of liquors
• Centrifugation… most common method
• Drying then required
• Filter/drier equipment, combines both processes
  Purity dependent on washing process

Question 27

Critical quality attributes of a product

Answer 27

Free from endotoxins
Container closure integrity
Free from foreign bodies
Accurate potency, correct formulation and isotonicity
Assurance of stability across the shelf-life
Correct labelling and packaging
Evidence that the product was made under appropriate controls defined by GMP
Free of micro organisms

Question 28

Active substance processes involve:

Answer 28

• Multiple steps involving molecular rearrangement (chemical processing)
• Cultivation and purification steps (biologics)
• Often complex, often long lead-time, normally low yield
   Chemical synthesis; protect people from the product
   Bioprocessing; protect product from people (contamination risk)
   Active substance processes can feel like ‘out of sight out of mind’:
• To QPs who are absorbed by the formulation process
• When the Active Substance is outsourced or manufactured overseas
• To QPs or SMEs who only visit the facility when there is a problem or during auditing

Question 29

What Quality Attributes would you want to be inherent in your medicine?

Answer 29

 Solid dosage forms
 PHYSICAL parameters important/critical
 Oral liquid products
 MICROBIOLOGICAL vulnerability – especially to water used
 Semi‐solid dosage forms
 MICROBIOLOGICAL issues often important
 Aerosols/metered dosage inhalers
 PHYSICAL and MICROBIOLOGICAL parameters important
 Injectable products
 For immediate onset of therapy
 CHEMICAL and MICROBIOLOGICAL purity important

Question 30

Issues for the API Manufacturer

Answer 30

Whilst in most bulk pharmaceutical chemical (API) manufacturing operations, chemicals or groups of
chemicals are synthesised using dedicated equipment, a range of therapeutically different APIs are
usually processed using the same equipment and the same premises. Physical and time segregation
helps to avoid cross‐contamination and mix‐up.
In certain circumstances, this practice of shared manufacturing facilities is contra‐indicated (e.g.
Cytotoxic agents, sensitising antibiotics, certain hormone products). Therefore, segregated, separated
(or in some cases isolated) facilities for both processing and packaging must be provided.
Cross‐contamination monitoring programmes and cleaning validation procedures will both be required
to assure the chemical quality of the product. Cross contamination and cleaning must be assured,
since analytical testing of the following API is seldom an option.
Setting of realistic and achievable limits will depend upon:
 The range of product and frequency of manufacture
 Relative ease of cleaning of equipment and premises
 Limits of detection of analytical equipment/methods
 Knowledge of clinical effects of products and other processing materials
 Metabolism and fate of the APIs

Question 31

The PHYSICAL characteristics (e.g. polymorphism and particle size) of an API are often critical to its
suitability for drug use, as these may affect…

Answer 31

 The ability to manufacture the medicine. The Flow properties of the API must enable handling/conveying/mixing to occur in the processing to make the dosage form
 The rate of absorption of the drug. The Solubilisation rate of the API is very importantly in the
way the drug is adsorbed into the body. This is referred to as BIOAVAILABLITY, which is
measured as part of the development of the dosage form known as pharmacokinetics. The
Particle size of the API may affect bioavailability and may also be very important, e.g. to allow
a micronised particle to convey/be propelled to the lung when using a Metered Dose
Inhalation product

Question 32

The major potential sources of microbial contamination are…

Answer 32

 Starting materials
 Process water
 Premises
 People

Question 33

Contamination Control Aspect

Answer 33

1 Plant and Process Design
2 Equipment and Facilities
3 Personnel
4 Utilities
5 Raw materials and IPCs
6 Containers and closures
7 Vendor Approval
8 Outsourcing
9 Process Risk Assessment
10 Process Validation
11 Planned preventive maintenance
12 Cleaning and disinfection
13 Monitoring
14 Prevention, trending, investigation, root cause analysis and CAPA
15 Continuous improvement

Question 34

API Micro requirements

Answer 34

 Clean… for non-sterile dosage forms, e.g. tablets ( <100cfu/g)
 Low bioburden… for use in injectable dosage forms ( 1cfu/g)

Question 35

API QP declaration
Formal requirement

Answer 35

 QPs have to declare Active Substances have been made in compliance with GMP and verify supply chain
* When MA application or variation is submitted
* Even when the variation has nothing to do with the Active Substance!
* De facto when releasing finished products

Question 36

2011/62 CONTROLS ON IMPORTATION

Answer 36

 For Active Substance suppliers outside EU, importation only allowed if accompanied by certificate of GMP compliance from regulatory authority in country of origin
 Regulatory agency controls must offer ‘equivalent level of protection of public health’ as EU authorities
 Commission to review acceptability of authorities at their request to allow exemption from certification
* Requires on site evaluation
* Repeat at least every 3 years
 Countries on the “white list”
* US, Japan, Australia, Switzerland, Brazil, Israel, South Korea,

Question 37

2011/62 CONTROLS ON IMPORTATION

Answer 37

 Clearly aimed at India and China
* Certificates are being issued
 Exception allowed where site inspected by EU and ‘to ensure the availability of medicinal products’
 Importers, Distributors and Brokers of Active Substances must register
* Users can only purchase from registered sources
* Distribution guidelines published (2015/C95/01)

Question 38

2011/62 EXCIPIENTS CONTROL

Answer 38

 Risk assessment required for excipients
* Level of GMP to be applied
* Risk assessment guidance issued… very onerous!
 Dosage form manufacturers to control suppliers (as per Active Substances)
* Including on site audit for high risk excipients!
 Regulatory agencies (US and EU) reserve the right of inspection
 NSF/IPEC/ANSI Guideline on Excipients based on ISO 9000 (363-2019)
* May be used as basis for control
 IPEC Good Distribution Practices Guide

Question 39

What is a Drug Master File?

Answer 39

A Drug Master File (DMF) is a means of presenting chemistry data to the regulatory authorities when
the ‘owner’ of the data is not the applicant for a marketing authorisation (Europe) or New Drug
Application NDA (USA) of a pharmaceutical product. The most usual reason for the use of the DMF
system is to protect the confidentiality of the scientific information supplied, but it can also help to
simplify submissions since a single DMF can be referenced for any number of applications.
The DMF System is used both in Europe and the United States. The API manufacturer submits the DMF
directly to the regulatory authorities and cross‐references the Marketing Authorisation Application
(MAA) or the NDA. Any questions arising during the assessment of the DMF are referred back to the
API manufacturer. Although the systems are essentially similar, there are some important differences,
ie:
 The EU system applies generally to active pharmaceutical ingredients (APIs) only
 The US system covers drug substances (APIs), drug products, packaging materials, excipients and other ingredients in drug products
 In Europe the MAA applicant receives information about the API from the open part of the EDMF. By the US system the NDA applicant does not have access to any information
 The US system at present includes provision for submission of details of the site of manufacture of the component or drug product concerned in a ‘Type 1’ DMF*. This is recommended for use only for overseas sites and is somewhat analogous to the Site Master File (SMF) required by the UK and some other European countries, using PIC/S format
 It should be noted that the FDA has raised the possibility of discontinuing the use of this ‘Type 1’ DMF, or of transferring ownership from CDER (Centre for Drugs Evaluation and Research) to ORA (Office of Regulatory Affairs), but this has not yet been taken fully forward. USA domestic sites have discontinued the use of Type 1 DMFs but the position for overseas companies is variable
In general, the DMF system can be used for any of the three types of API. They are:
 New APIs (new chemical entities)
 Existing APIs
 Pharmacopoeial APIs

Question 40

The European DMF (EDMF)

Answer 40

There are currently four options for the registration of active substances in Europe:
1. Certificate of Suitability of PhEur monograph (preferred option)
2. Full details of manufacture and QC of the drug substance from the Active Substance Manufacturer
3. European DMF
4. Other evidence of suitability of PhEur monograph in consideration of the qualification of impurities such as…
 Length of time on sale
 No significant process changes
 Named source has contributed to EU monograph
 Long and safe patient exposure
European guidelines on the DMF state that the…
“European Drug Master File (DMF) procedure may be used when the active ingredient manufacturer (AIM) is not the applicant for a product marketing authorisation (Applicant), with a view to protecting valuable know‐how on the manufacture of the active ingredient.”
A guideline on the European DMF procedure was incorporated into the Notice to Applicants, Volume 3A, in 1993. In September 2004 a Guideline on Active Substance Master File Procedure, EMEA/QWP/227/02, became effective. [The ICH CTD definition of an API is a ‘drug substance’ and in Europe the EDMF is also known as Active Substance Master File (ASMF)]
The route of application of the EDMF is dependent upon which procedure is being used for the MAA:

Question 41

There are 4 routes of application for MAAs:

Answer 41

 Centralised Procedure (i.e. via the EMA)
 Mutual Recognition Procedure: The procedure is for products which have a National Authorisation in one Member State. The MA application is made to further Member States in which authorisation is desired
 Decentralised Procedure: The procedure is available to products which have not been previously authorised in any Member State. The MA application is made to the Member States in which authorisation is desired, and one country (of the applicant’s choice) is requested to act as the RMS (i.e. via one member state and then mutually recognised by other states
 National (i.e. registered in one member state only)

Question 42

Structure and Content of a European Drug Master File (CTD format)

Answer 42

The EDMF should contain the sections of the MAA relating to the native substance (Section 3.2.S).
The EDMF is divided into two parts:
1 The Applicant’s Part (AP) – also known as ‘Open’ Part [CTD Module 3.2.S sections]
This part is intended to be available to the applicant for integration into the submission as part of
the marketing authorisation application. Sufficient information is provided to enable the applicant
to take responsibility for evaluation of the suitability of the active substance specification to control
the quality of the substance.
2 Restricted Part (RP) – also know as the ‘Closed’ Part
The Active Substance Manufacturer makes this part of the DMF available to only the regulatory
authorities. It contains details and comprehensive information on the synthesis of the active
substance and on the quality control during manufacture.

Question 43

Letter of Access [Annex 6.10 of EU‐CTD Module 1A]

Answer 43

A marketing authorisation applicant cannot cross‐refer to an EDMF without the consent of the
owner of the file.
The DSM must submit a ‘letter of access’ with the EDMF to the competent authorities for each
regulatory application that cross‐refers to his DMF. In addition, the applicant also must be provided
with the Letter of Access, the AP and the QOS for the AP.

Question 44

CTD: 2.3 Quality Overall Summary (QOS)

Answer 44

The Active Substance Manufacturer must also provide a summary and limited critical appraisal of the
data in the applicant‐restricted part of the EDMF, signed by an appropriate expert, is therefore
required.
In the same way that Module 3 of the main CTD must be accompanied by an expert signature (in
Module 1.4.1), the same requirement for expert sign‐off has to be fulfilled for the EDMF.
The criteria for selection of the expert are the same as those for selection of the expert for the
chemistry and pharmacy signature in the MAA. If an outside expert is used it is possible that
agreement could be reached for him to act as the expert for both the EDMF and MAA.
The structure of the QOS should follow the guidance given in the latest Notice to Applicants for
Module 2, section 3.
Other EDMFs
The CHMP guidelines relate to use of the EDMF system for active substances. However, the facility
to submit confidential data in a master file is not restricted to active substances. Some countries
accept data on other constituents of medicinal products or packaging materials (eg novel
ingredients, flavourings, fragrances or new primary packaging materials, especially polymers in
contact with the product) in the form of a DMF.

Question 45

European Pharmacopoeia Certificate of Suitability

Answer 45

An alternative approach to the EDMF is available for those materials where a PhEur monograph exists,
through the Certificate of Suitability (CEP) procedure.
This scheme is an alternative to the EDMF in that certification is accepted by the authorities in all EU
member states in lieu of submission of an EDMF. This of course means that there is a significant
advantage since only one certification dossier is required, instead of separate EDMF submissions in
many countries. It also has the advantage of showing that the active substance has obtained a CEP as
EDQM has a CEP database on its website. The CEP is valid for 5 years.
Like the DMF, the PhEur certification scheme used to be largely a paper exercise, not involving any
inspection of the active substance manufacturer. However, since the advent of 2004/27/EC in 2005,
EDQM have been coordinating GMP inspections by EMA for all CEP applicants.
The basis of the Certificate of Suitability (CEP) procedure is that an active substance manufacturer
can provide proof that the relevant monograph of the European Pharmacopoeia of the active
substance adequately controls its quality. In particular, this means that the monograph can control
the impurities arising from the method of manufacture. The certificate is issued by the certification
secretariat of the European Directorate for the Quality of Medicines and Healthcare (EDQM), which
is based in Strasbourg. (Generally the CEP is issued with qualifications that the active substance
manufacturer will test for parameters in addition to the PhEur requirements, eg residual solvents,
related substances, catalysts, etc) EDQM also consider further changes or elaborations of the PhEur
monograph (eg test methods/specification for other impurities, etc). CHMP now require current
requirements on impurity specification, even when PhEur Monographs do not meet ICH and
associated EU guidelines.
The Certification procedure can be used for the following products:
 Organic drug substances
 Inorganic drug substances
 Organic and inorganic excipients
 Products produced by fermentation as indirect gene products
 Herbal drug products and preparations
and
 All products with a risk of Transmissible Spongiform Encephalophies *used in the production
or preparation of medicinal products

Question 46

CEP New Procedures

Answer 46

1. The Note for Guidance on the European DMF Procedure proposes mandatory use of the
   Certificate of Suitability procedure for existing APIs, described in the European
   Pharmacopoeia. This will mean that if an API is the subject of a pharmacopoeial monograph,
   details of the control of the API within the MAA dossier will need to be provided by crossreference
   to an appropriate suitability certificate. A European DMF will thereafter be used for
   existing non‐Pharmacopoeial substances only.
2. All manufacturing sites, from active substance Starting Materials through to the active
   substance manufacturing site, will be identified on the CEP.

Question 47

CEP Data Requirements

Answer 47

The data required in the application primarily relates to the manufacturing method for the
substance and the impurities that are employed so that the suitability of the PhEur monograph can
be validated (Appendix 2). However the CTD format is also acceptable and it is usual for an EDMF
type document to be submitted.
Appendix 3 relates to TSE risk assessment. The key factor with TSE certification is traceability.
For both of these certification applications, expert reports (or CTD expert signatures and signed
Quality Overall Summaries) are required on the information provided.
In addition to the basic chemical information outlined in Appendix 2 and 3 an application form must
be completed.
As part of this, the ingredient manufacturer must make a number of declarations:
 A statement that manufacture takes place in accordance with a specified guideline on GMP
for the manufacture of raw materials and in accordance with the information presented. In
the case of TSE assessment it is accepted that suitable quality systems such as ISO 9000 or
HACCP may be accepted if GMP guidelines have not yet been elaborated
 A declaration of willingness to be inspected if required
 If an authorised agent submits the application, the manufacturer must provide a letter of
authorisation allowing the agent to act as an official representative. In this case the
authorised agent must also make a declaration of willingness to be inspected
Samples of one or two representative commercial batches of material are required in sufficient
quantity to perform a complete analysis. Samples of impurities may also be required if the
monograph does not control these.

Question 48

Active Pharmaceutical Ingredient (API)

Answer 48

Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal)
product and that when used in the production of a drug becomes an active ingredient of the drug
product. Such substances are intended to furnish pharmacological activity or other direct effect in
the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure and
function of the body.
Intermediate
A material produced during steps of the processing of an API which must undergo further molecular
change or purification before it becomes an API. Intermediates may or may not be isolated.
Note: This Guide only addresses those intermediates produced after the point that the company has
defined as the point at which the production of the API begins.
API Starting Material
A raw material, intermediate, or an API that is used in the production of an API which is itself or is
incorporated as a significant structural fragment into the structure of the API. An API Starting
Material may be an article of commerce, a material purchased from one or more suppliers under
contract or commercial agreement, or it may be produced in‐house. API Starting Materials are
normally of defined chemical properties and structure.

Question 49

API Quality management

Answer 49

Principles
 An appropriate quality system should be established in which quality is the responsibility of all
 Involves the active participation of management and personnel
 Covering organisation, procedures, processes, resources to ensure APIs meet established specifications
 Documented quality policy
 Covering responsibilities, authority and relationships
 All quality related activities defined
 Quality Assurance
 Viable systems for:
 Deviations
 Audits
 Maintenance
 Calibration
 Stability
 Complaints

Quality Unit(s)
 Quality independent of Production
 Authorised product – release personnel
 All quality related activities recorded
 Deviations from established procedures documented and investigated
 Quality evaluated before Batch Release
 Company officials notified of key issues e.g. investigations, recalls, regulatory actions and observations
 Approvals of:
 Specifications
 Master Process instructions
 Procedures
 Validation documentation
 Contract Manufacturers
 Changes
 Have adequate analytical control facilities

Production Responsibilities
 Developing procedures and instructions for processing
 Deviation reporting
 Maintaining premises and equipment records
 Executing calibration and validation
 Production of APIs
 Batch Records completion/review
 Facility/equipment cleaning/disinfection
 Change control evaluation
 Facility/equipment qualification

Question 50

API Internal Audits and Annual Product Quality Reviews

Answer 50

 Quality unit responsible for periodic internal audits findings
 Corrective actions documented and completed in a timely/effective manner
 Annual quality reviews of APIs, conducted, including:
 IPC and final product test results
 Process deviations and specification failures
 Changes carried out to processes or test methods
 Stability studies
 Complaints, recalls
 Adequacy of corrective actions
 Any revalidation and corrective action requirements

Question 51

API Personnel

Answer 51

Personnel Qualifications
 Adequate number of qualified personnel
 Education, training and experience
 Responsibilities/authority of key personnel documented
 Regular training with records maintained
 Effectiveness evaluated
 Training to include relevant GMP aspects

Personal Hygiene
 Practice good sanitation and health habits
 Appropriate clean protective clothing
 Avoid direct contact with APIs
 Smoking, eating, drinking etc. restricted
 Report relevant health problems (restrict activity)
 Only authorised personnel in limited access areas

Consultants
 Appropriately qualified and records kept of names/qualifications/experience

Question 52

API facilities

Answer 52

Design and Construction
 Facilitate cleaning, maintenance and operations
 Adequate space/material flow to avoid contamination and mix‐up
 Protected/closed equipment acceptable outdoors
 Defined areas for separate activities and security
 Adequate separated facilities for changing, washing etc.
 Microbiological contamination limited
 Laboratory areas normally separated
 In‐process test laboratories allowed in production areas if measurements not adversely affected

Utilities
 Critical utilities qualified and monitored
 Adequate ventilation for control of dust etc.
 Re‐circulated air permitted (with contamination control)
 Where APIs are exposed adequate air filtration, dust collection, exhaust system
 Pipework labelled (contents, flow direction)
 Adequate drains, with no back‐siphonage

Water
 Water suitable for intended use
 Potable or WHO water standard, as minimum
 Tighter chemical and microbial specifications may be needed
 Water treatment processes – validated and monitored
 Water for final stages of parenteral APIs – monitor and control of bioburden and endotoxins
Note: Guide does not formally stipulate specific Pharmacopoeial grades e.g. Purified Water,
Water‐for‐Injection, etc.

Containment
 Dedicated facilities, utilities and equipment for sensitising APIs (penicillins and cephalosporins)
 Also consider dedicated facilities for highly active or toxic APIs (certain steroids, cytotoxic agents)
 Measures to prevent cross‐contamination
 Segregate highly toxic non‐pharmaceutical activities

Lighting
 Adequate

Sewage and Refuse
 To be properly disposed of and identified

Sanitation and Maintenance
 Buildings should be kept clean and properly maintained
 Written procedures required
 Pest control procedures required

Question 53

API process equipment

Answer 53

Design and Construction
 Qualified, appropriate design, size and location for its use, cleaning and maintenance
 Contact surfaces, non‐reactive, additive or absorptive
 Formal IQ/OQ
 Identify all major equipment
 Limit product contact with operating substances e.g. lubricants, coolants
 Food grade lubricants and oils used
 Use closed equipment where feasible
 For open equipment, avoid contamination
 Sets of as‐built drawings maintained

Equipment Maintenance and Cleaning
 Preventative maintenance required
 Written procedures required for cleaning and maintenance
 Carry over of impurities should not affect impurity profile
 Cleaning at appropriate intervals for successive batches of same material
 Change‐over product cleaning
 Cleaning methods, agents and residue levels defined and justified and clear labelling of all equipment

Calibration
 Quality critical equipment to be routinely calibrated
 Written procedures, records retained
 Calibrations traceable to certified standards
 Current calibration status apparent
 Equipment out‐of‐calibrations should not be used
 Investigate deviations and assess impact

Computerised Systems
 Computerised systems to be validated
 Depth depends upon criticality
 Public domain software, lower requirements
 Retrospective validation for existing systems
 IQ and OQ for hardware and software – less for commercially available
 Prevent unauthorised access or changes (Data, Software, Hardware)
 Written procedures for all key operations
 Double‐checking of critical data entry (second operator or computer itself)
 Deviation investigation and change control systems
 Back‐up for critical records

Question 54

API documents and records

Answer 54

Documentation System and Specifications
 Documents to be prepared, reviewed, approved and distributed following a written procedure
 Superseded documents and revision histories to be controlled
 System established for retaining all appropriate documents
 Record retention
 At least one year after expiry date of batch
 For API with retest date, three years after batch is distributed
 Records available for inspection/copying by Authority at site
 Transfer from other location acceptable, if prompt
 Records as originals or true copies (including micro film, electronic)
 Hard copies must be readily available. Electronic signatures are acceptable
 Good documentation practice required

Equipment Cleaning and Use Records
 Written records of cleaning and maintenance for major equipment items
 Persons performing/checking to date and sign
 Record of usage of major equipment items
 Date, time, product, batch numbers
 Reduced records for dedicated equipment

Question 55

Raw Materials, Intermediates, API Packaging Materials and API Labelling Records

Answer 55

 Written procedures for material control
 Records should include
 Delivery information (identity, quantity, code, supplier, date etc.)
 Results of any tests (and conclusions)
 Inventory record for RM and Intermediates reconciliation
 Proof of conformity of labels and containers
 Disposition of rejected materials
 Master labels required for comparison to issued labels

Master Production and Control Records
 Written procedure for preparation
 For each material, batch size
 Signed and dated (electronic is OK)
 Independently checked by second person (signed/dated)
 To include all key process information
 Name of material
 List of raw materials/intermediates required
 Quantities or ratios of each
 Plant and equipment definition
 Details of process to be followed
 Special features or precautions
 Storage/packaging information

Batch Production and Control Records
 Required for each batch (unique Batch Number)
 Confirmed copy of master records (signed/dated)
 Confirmation that each significant step was carried out
 Manufacture, control packaging’s
 When and by whom
 Materials, equipment, sampling, test results, yields
 Label control records, with specimens
 Deviation investigations and results
 Results of release testing
 For computer controlled operations hard copy records may not be required

Laboratory Records
 Records of analytical tests
 Including preparation and testing
 Reference standards, reagents, standard solutions
 Any modification of standard methods
 Complete data from tests
 Description/identification of samples
 Methods used and their validity
 All raw data, properly identified
 Calculations
 Statement of test results
 OOS investigations
 Signed/initialled and dated
 Checked by second person (signed/dated)

Production Record Review
 Batch production and control records for critical process steps
 Reviewed and approved by Quality Unit to determine compliance with procedures and specifications
 Earlier, non‐critical process steps
 Reviewed by qualified production or other personnel following procedures approved by Quality Unit
 May be released by production (unless for external shipment)
 Investigation of discrepancies and failures (involving Quality Unit)
 Formal procedure, written records report, conclusions actions
 Deviations, OOS results, investigations to be included in batch records

Question 56

API Materials management

Answer 56

General Controls/Purchasing
 Written procedures for raw materials
 Purchase, receipt, identification, quarantine, storage, handling, sampling, testing approval or rejection procedures to be followed
 Raw materials purchased against agreed specifications
 From approved suppliers
 Reduced testing allowed for “good suppliers”
 C of A and identity test as minimum
 Evaluation system for critical RM suppliers
 The manufacturer of the RM should be known (if not the supplier)
 Changes in sources should be controlled

Receipt and Quarantine
 Initial examination before acceptance
 Correct labelling, damage, contamination, etc.
 Formal clearance of bulk materials before mixing
 E.g. solvents, bulk silo stocks
 Procedures to prevent discharge to wrong stocks
 Evidence of cleaning of non‐dedicated tankers
 RM containers distinctly identified
 System for batch status identification
 Storage containers, lines, etc identified

Sampling and Testing of Materials
 Each batch tested and released for use (or rejected)
 Sampling based on scientific criteria (but a minimum of one test)
 Area and procedures to avoid contamination
 Sampled containers to be re‐sealed and marked
 Identification test for each raw material
 Full testing, if no C of A is available (>three full analyses before accepting C of As)
 Testing of hazardous or toxic RMs not essential
 Retesting of RMs after defined storage period
 Including large storage containers
 Recovered solvents tested against appropriate specification

Storage
 Raw materials stored to prevent contamination
 Boxed/bagged materials stored off the floor
 Outdoor storage of suitable materials allowed
 Quarantine of raw materials until released
 Approved RMs stored in controlled conditions
 Oldest stock used first (FIFO)
 Rejected materials identified, quarantined and controlled
 Re‐evaluation date needed

Question 57

API Production and In‐Process Controls

Answer 57

Production Operations and Time Limits
 Written procedures established and followed for process controls
 Dispensing activities
 All in‐process controls, tests and examinations
 All steps in process
 Reviewed/approved by Quality Unit
 Results documented at time of performance
 Deviations recorded and explained/investigated (including OOS procedures)
 Critical steps should be verified
 E.g. RM identification and weighing, weighing properly controlled and weighed materials properly identified
 Yields determined at appropriate stages
 Deviations from expected to be investigated
 Contents of major equipment items to be identified
 Equipment items used to be recorded
 Time limits for processing steps
 Storage times and conditions for intermediates established
 Materials for reprocessing/reworking, quarantined

In‐process Samples and Controls
 From R&D work
 In‐process controls and limits documented (QA approval of critical points)
 May be carried out by qualified production personnel under QA approved procedures
 Results recorded in Batch Record

Blending of Batches
 Blending is acceptable, if controlled and documented
 To ensure uniformity or facilitate processing
 Each batch in final blend
 Manufactured by approved process, meets appropriate specification, traceable in final blend records
 Blending to disguise out‐of‐specification materials
 Not acceptable
 Blending processes to be validated to show homogeneity
 Controlled blending of acceptable tailings allowed
 Stability testing of final blended batches must be conducted if there is a risk of instability

Contamination Control
 Carry‐over from successive batches of same material is OK, if controlled
 Contamination at all stages to be avoided
 Special care for pure/final APIs

Question 58

API packaging and labelling

Answer 58

General
 Written procedures established and followed
 Receipt, identification storage, testing etc.
 For API containers, closures, labelling and packing materials

Packing Materials
 Containers and closures to provide adequate protection
 Clean and non‐reactive, etc.
 Re‐used containers, cleaned by documented procedures
 Previous labels removed or defaced
 Labels and packaging materials
 Sampled, tested and released before use

Labelling Issuance and Control
 Limited access to storage areas
 Reconciliation procedures for labels
 Discrepancies investigated (with QC Unit approval)
 Excess labels destroyed, when batch identified
 Controlled procedures for returned labels
 Obsolete labels destroyed
 Separation from other API operations
 Facilities inspected for clearance before use (documented)
 Issued labels checked and documented
 Printing devices used in packaging operations to be monitored
 Documented check of final API packaging and labelling
 Sample of labels used to be retained

Packaging and Labelling Operations
 Documented procedure to ensure use of correct materials
 Tamper evident sealing of API containers
 Labels of API containers should show name and address of original manufacturer
 Plus any re‐packer, re‐labeller or processor

Question 59

API Storage and Distribution

Answer 59

Warehousing Procedures
 Appropriate storage conditions for all materials
 Records for critical conditions
 Separate storage areas to prevent use of:
 Quarantined, rejected, returned, recalled materials
 Or alternative systems of control

Distribution Procedures
 Quality Unit evaluation prior to release
 Manner of distribution to maintain quality
 Special conditions indicated on label
 Distribution records to enable recall, if necessary

Question 60

API Laboratory Controls

Answer 60

Independent, Adequate Laboratory Facilities/Batch Testing and Release for Distribution
 Documented procedures for sampling, testing, disposition
 Each batch of intermediate or API
 Laboratory tests to determine conformance to specification
 Out‐of‐specification results investigated and documented
 Re‐sampling and re‐testing to documented procedures
 Data analysis, assessment, actions, report
 Records to be maintained
 Specifications and procedures to be scientifically sound and approved by the Quality Unit
 Secondary reference standards to be qualified
 Testing performed for impurities
 Volatile organics, other major and microbiological (if appropriate)
 Impurity profile to be carefully controlled
 Check against regulatory submission/historical data

Certificate of Analysis
 Issued for a specific batch of API
 Batch number, dates (manufacture, analysis, expiry)
 Test results and acceptance limits
 Information on original manufacturers, re‐packers, analytical laboratory
 Electronic signatures acceptable, if authenticated and secure

Stability Testing of APIs
 Documented ongoing programme (as per ICH Guidelines)
 Batches, size, test intervals
 Storage conditions
 Additional stressed samples
 Stability indicating test methods (validated)
 Minimum of three batches in long term programme
 Pilot scale acceptable initially, if representative
 First three commercial batches then included
 One additional batch annually is normal
 Containers as market containers
Note: More frequent stability testing is required for short shelf life APIs (less than one year expiry period).

Expiry and Retest Dating
 C of A or labels to specify an expiry or retest date
 Preliminary dates based on pilot scale batches
 Retain samples required for retest purposes

Reserve/Retention Samples
 For future evaluation only
 Identified sample of each API batch kept:
 One year after expiry/retest date
 Or three years after distribution
 Stored under label conditions in ‘market’ containers (or better)
 Annual visual examination. Investigate any deterioration
 Sufficient for two full analyses

Question 61

API Validation

Answer 61

Validation Policy
 Company’s overall policy should be documented
 Critical process parameters identified during development
 Ranges defined
 Validation should extend to those process steps determined to be critical to the:
 Quality and purity of the final API
 Critical product attributes of API defined
 Critical process steps defined
 Impurity profiles confirmed

Validation Documentation
 Validation Protocol established
 What will be done, how and by whom
 Acceptance criteria defined
 Approved by Quality Unit
 Validation Report
 Refers to Validation Master Plan and Protocol
 Results and conclusions
 Process validated or further actions proposed

Qualification and Process Validation Programmes
 Activities subdivided, DQ, IQ, OQ, PQ, PV
 Critical instruments, calibrated (beforehand)
 Critical facilities, utilities and systems qualified (beforehand)
 Prospective validation for new processes (preferred)
 Concurrent validation for infrequent processes (normally three batches)
 Retrospective validation for established processes, by exception (10 – 30 batches)
 Impurity profile should be evaluated
 Validation re‐evaluated periodically

Cleaning Validation
 Cleaning methods should normally be validated
 Direct at situations posing greatest risk, including cleaning agents
 Detailed validation protocol required
 Scope, responsibility, methods, parameters, sampling defined analytical methods, acceptance criteria, etc., defined
 For sets of similar cleaning processes/products
 Validate worst case situations
 Residue limits should be practical, achievable and verifiable
 Based upon pharmacological or physiological activity
 Establish recovery level of cleaning methods and validate analytical

Validation of Analytical Methods
 Required unless Pharmacopoeial or other official method
 Follow ICH guidelines
 Extent dependent on purpose of analysis
 Qualify equipment beforehand
 Modifications to methods must show equivalence to original

Change Control
 Formal change control system established and documented
 Covering significant changes in all areas
 Changes drafted, reviewed and approved by QC Unit
 Classification scheme suggested
 Major (having an impact on critical quality attributes)
 Minor (unlikely to have an impact on critical quality attributes)
 More validation effort for major changes
 Revise all documents affected by the change
 Evaluate first batches after a change
 Consider effect on retest or expiry dates
 Additional stability samples
 Notify dosage form manufacturers

Question 62

API Rejection and Re‐use of Materials

Answer 62

Rejection
 Rejected materials identified and quarantined
 Reprocessing or reworking can be allowed on the basis of:
 Documented procedures
 Materials must meet appropriate specifications
 Disposition of rejected materials recorded

Re‐processing
 Infrequent repeating a step in an established process, acceptable however
 IPC ‘completion of reaction’ tests – part of normal process
 Reprocessing un‐reacted material should be carefully evaluated

Re‐working
 Using different procedures from the established process
 Extensive investigation, review, approval, documentation
 Concurrent validation may be required
 Extensive testing to ensure conformance
 Compare impurity profiles
 Stability testing possibly required

Recovery of Materials and Solvents
 Secondary recovery of reactants, intermediates or API is acceptable
 If approved procedures exist
 If recovered materials meet suitable specifications
 Fresh and recovered solvents or reagents may be combined
 If testing confirms suitability
 Must be adequately documented

Returns
 Returned APIs identified and quarantined
 Reprocess, rework or destroy if any doubts
 Accept only after thorough examination
 Proof that product still meets specification
 Records to be maintained
 Where from?
 Why?
 Final disposition by Quality Unit

Question 63

API Complaints and Recalls

Answer 63

Complaints
 All complaints recorded and investigated, under written procedure
 Records retained
 Action taken
 Trend evaluation, corrective actions

Recalls
 Written procedure
 Defines circumstances, responsibilities, evaluation
 Details procedure, persons to be informed
 How recall material should be treated
 Serious situations, local or national authorities informed

Question 64

API Contractor/Manufactures (Including Laboratories)

Answer 64

 Manufacturers or laboratories must comply with ICH Q7 GMP and should be evaluated
 Written approved contract defining responsibilities
 Including right to audit
 No sub‐contracting without approval
 Records kept and available to contract giver
 Contract giver is ultimately responsible for change control

Question 65

API Agents, Traders, Distributors, Brokers, Re‐packers and Re‐labellers

Answer 65

 Traceability is paramount
 Pharmaceutical Quality System documents required
 Care/appropriate facilities for repacking
 Stability data to support expiry dates
 Full transfer of original information
 Complaints and recall system needed
 Must comply with ICH Q7 GMP

Question 66

Special Biotech Considerations – APIs Manufactured by Cell Culture/

Answer 66

Fermentation
 General
 Cell Bank Maintenance and Record Keeping
 Fermentation
 Harvesting
 Isolation
 Purification
 Viral removal/inactivation

Question 67

APIs for Clinical Trials

Answer 67

General
 Appropriate Quality Unit and GMP concepts applied
 Suitable approval mechanism for each batch
 Manufacturing practices consistent with the stage of development
 Flexibility of process and analytical methods
 Products for clinical trials
 Manufacture in suitable facilities
 Appropriate procedures and controls
 Ensuring safety, quality and homogeneity of API

Quality
 Independent Quality Unit still needed
 Approval or rejection of each API batch
 Other ‘usual’ functions, may be performed elsewhere
 System of testing still needed for
 Raw materials, packaging materials, intermediates and APIs
 Labelling of APIs for trials appropriately controlled
 Identified as for investigational use

Equipment and Facilities
 Procedures to ensure equipment is calibrated, clean and suitable for use
 All phases, all scales of facility
 Contamination to be avoided (all phases, all scales)

Control of Raw Materials
 Raw materials used in early stages of clinical API production
 Evaluate by testing
 Or supplies C of A and identity test
 Raw materials from new supplier, accepted on
 Use testing, rather than analytical testing alone

Production and Process Controls
 Laboratory notebooks or batch records may be used
 To document production of clinical APIs
 All pertinent information to be recorded
 Yields more variable and less well defined

Validation
 At early clinical stages only limited process validation may be possible
 If number of batches of APIs are limited, then extensive in‐process and product testing may be used
 More comprehensive process validation as additional batches are produced, under replicated conditions
 Pilot or small scale manufacturing continued indefinitely should be validated
 When processes are scaled up, full validation of the commercial production process

Changes
 Changes are expected during clinical development
 All process modifications should be documented

Laboratory Controls
 All analyses should be scientifically sound
 A system for retaining reserve samples should be used
 For appropriate time after approval or termination of an application
 Expiry or retest date should be established

Documentation
 Information on development and production of APIs for CTs
 Should be documented
 Integrated into process development report
 Development and implementation of analytical methods documented
 All modifications documented
 Production and control records retained
 For appropriate time after approval or termination of an application

Concluding Remarks
In the sections above, specific points of GMP relating to Active Pharmaceutical Ingredients have
been summarised. The reader is reminded, however, that the legal basis for Current Good
Manufacturing Practices remains:
 European Union (EudraLex)
The Rules Governing Medicinal Products in the European Community. (EudraLex Volume 4).
Good Manufacturing Practice for Medicinal Products. GMPs for APIs are Part II.
 United States
Chapter 21 of the Code of Federal Regulations, Parts 210 and 211 GMP for Medicinal
Products.
Thus, in addition to the specific points concerning APIs discussed above, all general
procedures and standards which can be reasonably be applied to APIs, must also be
followed.

Question 68

API GMP

Answer 68

GMP for Level 0 – 1
Application to – critical raw materials (e.g. API Starting Materials) Requirements
 A basic quality management system, e.g. ISO 9000
 Basic GMP principles e.g. clean‐out procedures, traceability, lot control and full specification of the material.

GMP Level 1
Application to – early stages of synthesis GMP Documentation: basic only
 Simple instructions
 Generally no double checks
 Good recording practices
 Lot traceability
 Archived on completion
 Defined processes and SOPs

Requirements
 Raw materials identify only, with Certificates of Analysis
 Limited in‐process/end product testing
 Personnel training in GMP
 Equipment installation and checks to good engineering practices (GEP) only
 Calibrations of measuring and test equipment
 Verification of test methods (scientifically sound analytical practices)
 Change control and self‐inspection
 Verification of cleaning procedures
 Good packaging and labelling standards
 Deviations recorded and impact assessed

GMP Level 2
Applicable to:
 Pivotal key intermediates (significant structural fragments)
 Critical process stages (those containing critical processing parameters or operations)
 Key stages of synthesis (those where impurities emerge or are eliminated) Requirements: as for Level 1, plus
 Control of critical raw material suppliers
 Enhanced specifications for raw materials and intermediates
 Detailed documentation
 Checks of critical steps
 Qualification of equipment and critical utilities (DQ, IQ, OQ Studies)
 Validation of processes, cleaning and test methods
 Deviation and OOS systems

GMP Level 3
Applicable to:
 Final stages of synthesis
 Final API process step(s)
 Harvesting solvent‐wet API
 Isolation of API
 Final handling of API
 Drying
 Milling/micronisation/sieving
 Blending
 Packaging

Requirements: as for Levels 1 and 2, plus
 Environmental control
 API stability testing programme
 QA release of batches (after review of the whole batch pedigree/genealogy) GMP Level 3 satisfies all the requirements of Sections 1 – 18 ICH Q7.
 Equivalent to facility and environmental standards at the dosage form manufacturer in the areas into which the API is introduced.
The key message is that the system for application of GMP does not change. Personnel do not need to
be trained to follow different approaches, but simply to follow the requirements as defined at each
stage.

GMPs and Quality Assurance for Sterile APIs
Introduction
1. Available Guidance on GMP Requirements
The following sources of guidance are considered:
 EudraLex Volume 4 – Part I
 Annex 1 – Manufacture of Sterile Medicinal Products
 Annex 2 – Manufacture of Biological Medicinal Products for Human Use
 EudraLex Volume 4 – Part II
 Part II text: Basic Requirements for Active Substances used as Starting Materials
 4.34 non‐steriles APIs used to produce a sterile drug
 FDA “Aseptic Processing Guidelines”, last updated 30‐April‐2009
 APIC “Manufacture of sterile active pharmaceutical ingredients”
 PDA “Technical Report No 28 “Process simulation testing for Sterile Bulk Pharmaceutical Chemicals”

2. General Principles for Sterile API Manufacture
    Where the dosage form is required to be sterile, the API should be sterile – unless the dosage form is:
    Terminally sterilised, or
    Produced by a process which includes sterilising filtration
    APIs for use in parenteral products must comply with specifications on bacterial endotoxin
    API manufacture should be controlled for bioburden
    Focus on contamination avoidance and bioburden control
3. Premises, Utilities and Equipment
    Designed to provide assurance of:
    Product protection
    Operator safety
    Containment
    Achieved by:
    Air filtration
    Air pressure differentials between incompatible zones
    People, process, materials and waste flows for segregation
    Operator education, training, discipline and supervision
    For aseptic processing, the principles of EU Annex 1 and the FDA’s “Aseptic
   Processing Guide” apply
    For biologicals API manufacturing, the principles of EU Annex 2 apply
    Risk of cross‐contamination may require precautions such as:
    Dedicated facilities
    Campaign production
    Closed systems
    Measures adopted should be based on documented risk assessment
    Positive pressure areas to be used to process sterile products, but… negative pressure in specific areas acceptable for containment reasons in biologicals production
4. Cleaning and Sterilisation
    Cleaning
    Automated systems rather than manual procedures preferable
    Cleaning should be validated
    Sterilisation
    Sterilisation by heat/SIP is the method of choice for equipment
    Product sterilisation is normally by filtration, but could be by terminal processing
    Sterilisation processes should be validated
    Layout and design of production areas and equipment should permit:
    Effective cleaning
    Decontamination
    Equipment should be designed to facilitate:
    Cleaning
    Sterilisation
    Encourage use of systems for:
    Clean in place
    Sterilise in place
    Cleaning and decontamination procedures should be validated
5. Low Molecular Weight APIs – Specific Considerations
    Convert non‐sterile drug substance to sterile API
    Dissolve, subject to 0.2μ filtration
    Aseptic precipitation or crystallisation
    Aseptic isolation (centrifugation, filtration)
    Aseptic drying, milling, blending
    Aseptic sampling packaging
    Activities in closed systems or by validated aseptic processing
    Multiple process steps must be integrated, including product transfers
    Equipment often not originally designed for sterile processing
    Increasing use of isolators or barrier techniques
    Aseptic processing must be confirmed by media simulations
    Very difficult!
    Typically requires two stages
    Liquid processing
    Solids processing
    Incubate and examine all of the media or a sample?
    Possible terminal sterilisation
    Irradiation at >25kGy if product stable
    Possible dry heat treatment, but many products not stable at required temperatures
    Historic use of gas techniques such as ethylene oxide, but these are not penetrating
6. Packaging
    Fill aseptically or terminal sterilisation
    Must maintain product sterility
    Multiple sterile bagging to facilitate transfer to dry powder filling operations
7. Choice Quotes from FDA Inspection Guidance
    Microbiological as well as endotoxin data on critical components and operational steps should be reviewed
    In the spray drying of sterile powders there are concerns
    Equipment or sterile bulk drug substances should be sterile and capable of being sterilised
    Sanitisation rather than sterilisation is unacceptable
    Method of choice for sterilisation is clean steam (SIP) Use of formaldehyde is a much less desirable method
    Only Water for Injection should be utilised (concern for endotoxin cited)
    Single pass RO + post‐RO sterilizing filters unacceptable
    Sterilising filters unacceptable in WFI system
    The use of ethylene oxide as a primary means of sterilisation is unacceptable
    Reprocessing procedures should be validated
    Sterilisation by radiation is the method of choice for plastic bags

Question 69

Active Substance (AS) Impurities

Answer 69

Introduction
Considerable emphasis is placed by the regulatory authorities on control of the impurity profile for
active ingredients. This is reflected in the GMP guidelines for ASs, where much attention is given to the
application of systems and procedures during AS production to ensure the purity of the AS.
The focus of this attention is two‐fold…
 Control of processing operations to control/minimise the generation of impurities with accompanying conditions to prevent contamination
 Removal of impurities by specific purification methods
To do either of these effectively requires a sound understanding of the AS production process and the
ways in which impurities can be generated or removed.

Classification of Impurities
The ICH Q7 GMP guideline for ASs requires impurities to be classified as inorganic, organic or solvents.
It also requires that an impurity profile describing the identified and unidentified impurities present in
a typical batch of the AS be established, and that impurity profiles be periodically reviewed against the
impurity profile in regulatory submissions in order to detect changes due to modifications in the
production process.
ICH Guidelines have been developed in the last 10 years which provide more detail of limits for
impurities and also now expect a level of risk assessment to determine appropriate limits. (See Process
Contaminants section).

Types and Sources of Impurities
For AS manufacturers it is most relevant to consider that impurities are likely to originate in two major
ways, as either:
 Related substances: by‐products or degradation products formed during the reaction or during storage, structurally related to the drug substance
 Process contaminants: impurities unrelated to the drug substance which may be:
 Process specific, eg reagents, solvents, catalysts etc.
 Process independent, e.g. foreign matter, residues from dirty equipment, environmental contaminants etc. (NB USP proposes suitable tests be used for detecting certain impurities from extraneous sources! (Ref 4))

Related Substances
Control of related substances will depend on many factors, including:
 Process design and development and its scale‐up to production. The need for good communication between development and production staff cannot be emphasised strongly enough. It is essential that development personnel understand the constraints and limitations that exist in production. This information should be used to develop data to substantiate appropriate ranges for critical process parameters
 Process validation and control during routine production. Validation should be used to establish working limits (operating ranges) for variable conditions. These should be able to be achieved reproducibly using the equipment and process concerned. They should have been shown by the development and scale up process to be safely within ‘edge of failure’ limits, beyond which acceptable quality product will not be obtained.
 Confirmation of the impurity profile obtained over the range of these working limits represents an important aspect of process validation. It is essential that the impurity profile of routine production is not significantly different from the batches used in toxicological and clinical studies
 Control of raw materials; raw material quality and impurities can obviously have a major impact on AS product quality. Concerns over the establishment of good supplier relationships are just as significant to the AS manufacturer as they are for dosage form manufacturers There has historically been general agreement that related substances up to the level of 0.10% can generally be tolerated in ASs without elucidation of their structure and the development of specific data concerning toxicity and pharmacology.

This norm has been effectively endorsed by the International Conference on Harmonisation (ICH) who has published guidelines concerning impurities in new drug substances (Ref. 1, 2, 6, 7) which identify the following requirements to be met when marketing approval is being sought:
 Reporting threshold is 0.05% for ≤ 2g maximum daily dose (0.03% if  2g)
 The Structure of Impurities should be characterised – if present at  0.10% at ≤ 2g maximum daily dose (or 0.05% if  2g)
 Degradation products also to be identified if they are present at  0.10% (during storage period)
 Impurities below 0.10% to be identified if unusually potent, toxic or have a pharmacological effect
 There is an obvious need for appropriate analytical methods
 Qualification of impurities is defined as the process of acquiring and evaluating data which identifies the structure, and establishes the biological safety, of an individual impurity or a given impurity profile, ie structured characterisation and Toxicity Studies
 Qualification threshold has been established based upon likely daily dose. Less than or equal to 2g per day qualify at 0.15% or 1.0mg per daily intake, whichever is lowest. Above 2g per day qualify at 0.05%
In reality the limit depends upon many factors:
 Pharmacology of both the product and the impurity
 The therapeutic regime, i.e. the dose, its duration, the route of administration etc.
 The target patient population, i.e. any special risks etc.
 The cost of qualification studies

Question 70

Pharmacopoeial Monographs

Answer 70

Whenever an AS is the subject of a pharmacopoeial monograph, then the quality of the AS must comply with all the impurities requirements of that monograph:
 For AS used in USA, not only does the AS need to comply with its USP monograph, but also other general requirements, eg those of Impurities in Official Articles and Residual Solvents/Organic Volatile Impurities
 For AS used in Europe, dosage form users are required to follow Ph.Eur. Monograph ‘Substances for Pharmaceutical Use’ and Chapter 5.10 ‘Control of Impurities in Substances for Pharmaceutical Use’. Specifically, each user must ensure that any impurity in the AS from each source which is not a specified impurity in, or a detectable impurity of, the monograph method, has been formally evaluated with respect to dentification/qualification (safety) issues

Question 71

API Process Contaminants

Answer 71

Process contaminants may be:
 Chemical
 Physical
 Microbiological

Chemical Contamination is likely to arise from two major sources:
1. Contamination from the manufacturing process; possibly with by‐products, degradation products, genotoxic impurities, trace elements, residual reagents, solvents or catalysts etc. Measures to control such contamination are essentially the same as to control related substances.
Process control is especially important, for instance to ensure the completion of reactions and thus the absence of residual starting materials or reagents, controlled drying to completely remove solvents but not degrade the product etc.
An ICH Guideline Q3C has also been issued in 2005 on residual solvents.
This identifies controls as follows:
 Residual solvents are classified by a health risk assessment or Tolerable Daily Intake (TDI) based upon a 2g daily dose. From this a level is set for Permitted Daily Exposure (PDE)
 Class 1 Solvents – Solvents to be avoided e.g. known or suspected carcinogens, environmental hazards such as Benzene
 Class 2 Solvents – Solvents to be limited e.g. non‐genotoxic carcinogens or causative agents of irreversible toxicity such as Toluene, Methanol, Hexane etc. ADIs are given in mg per day and ppm. Depending
upon the solvent, their typical ranges are:
ADIs ‐ 0.5 to 50mg
ppm ‐ 50 to 5000
 Class 3 Solvents – Solvents with low toxic potential e.g. low toxic potential to man but should be limited on GMP or other basic quality requirements eg Acetic Acid or Acetone Levels below 50mg per day or 5000ppm acceptable without justification Levels above this figure can be accepted if justified
 Class 4 – Additional solvents
Some solvents (such as petroleum ether, Iso‐octane etc.) could not be classified as data is unavailable. Manufacturers must justify their own limits of unlisted solvents that may be present as residual solvents
An ICH guideline (Q3D) on elemental impurities (metal contamination) was approved in December 2014. This addresses catalyst residues as well as metals from other sources.
The guideline applies to new finished drug products (as defined in ICH Q6A and Q6B) and new drug products containing existing drug substances. It presents a process to assess and control elemental impurities in the drug product using the principles of risk management as described in ICH Q9. This process provides a platform for developing a risk‐based control strategy to limit elemental impurities in the drug product.
The philosophy behind the guideline is that elemental impurities do not provide any therapeutic benefit to the patient, therefore their levels in the drug product should be controlled within acceptable limits. There are three parts of this guideline:
1. The evaluation of the toxicity data for potential elemental impurities;
2. The establishment of a Permitted Daily Exposure (PDE) for each element of toxicological concern;
3. Application of a risk‐based approach to control elemental impurities in drug products.
The guideline provides a classification of the elements based on their toxicity and likelihood of occurrence in the drug product.
 Class 1 – As, Cd, Hg and Pb
 Class 2a – Co, Ni, V
 Class 2b ‐ Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se and Tl
 Class 3 – Ba, Cr, Cu, Li, Mo, Sb, and Sn (Only consider for parenteral and inhalation products (unless intentionally added)
 Other Elements: Al, B, Ca, Fe, K, Mg, Mn, Na, W and Zn
Application of Q3D to existing products was given more than 36 months to implement after publication of the guideline by ICH and is now fully in force.

2. Cross contamination which may arise from:
    Ingress of lubricants, seal fluid or heat transfer fluids
    Inadequate cleaning of equipment and containers
    Inadequate separation of activities
    Poor ventilation, particularly where powders are handled
    Poor segregation, packaging and labelling of materials
    Inadequate maintenance of equipment, e.g. leaking bearings, corrosion etc.
   Physical Contamination generally arises from one of four main sources:
    Raw materials, reagents, solvents. Sieving or filtration of these materials as part of the charging operations is a prudent precaution. Special precautions must be taken for raw materials of geological origin which cannot be purified by chemical methods. For example, lime which is suspended in water and then fine sieved to remove other minerals/rocks
    The production environment: Physical contamination of material from the general production environment is perhaps the least common form of contamination and as such may be the most difficult to trace. The major causes are:
    Poor ventilation
    Inadequately maintained building fabric, especially overhead services etc.
    Inadequate insect and pest control
    Inadequate plant housekeeping
    The production equipment: A very common cause of physical contamination, such as:
    Disintegrating gaskets, O‐rings, screens etc.
    Rust particles
    Nuts, bolts and other component parts
    Metal swarf generated by rubbing and wearing
   All the above emanate from inadequate equipment maintenance, or inadequate design, e.g. incompatibility to aggressive reagents, solvents
    The production personnel: The production personnel constitute probably the most common and certainly the most easily preventable source of physical contamination to ASs. Examples of common forms of such contamination include:
    Pens, screwdrivers etc.
    Personal items
    Clothing
    Residues from raw material packaging

Microbiological Contamination is typically not a major problem in synthetic chemical processes. These processes are generally carried out in closed systems so that the potential for atmospheric contamination is very limited and, in addition, the processing environment is often very hostile to microorganisms. Where a problem does exist with these processes it is most often attributable to the use of water in the late stages of the product isolation and purification and thus appropriate controls must exist over the quality of the water used in these process steps.
Microbiological considerations are however highly important when the starting material or the raw material is of biological or geological origin.
Biological materials may be derived from plant or animal materials or from culturing techniques. Once again the subsequent processing steps will typically involve aggressive reagents and solvents which will reduce native bioburden, but not necessarily pyrogens, and late stage purification procedures may need to be especially designed to completely remove any such residual contaminants. This is also true for excipient materials such as talc which may be mined. Aggressive washing methods (such as with acid) may be necessary, not only to remove inorganic impurities, but also to control bioburden.
Consideration must be given to the end use of the product in determining appropriate microbiological control procedures to be applied, thus the standards for materials for oral use may not be as rigorous as those for instance for topical or inhalation products or those to be subsequently sterilised. Of course, standards for materials produced as sterile AS bulks must be designed to ensure sterility at all times and must include appropriate environmental controls.

Essential Messages
What measures can therefore be taken by the supplier and by the pharmaceutical manufacturer to
enhance the purity of ASs?
The AS Supplier
The potential for contamination may be minimised in several ways:
 Control of starting materials
 Strict adherence to defined and validated manufacturing and purification processes
 Reporting of unexpected deviations from the norm
 Appropriate segregation of activities and products
 Careful attention to washing and cleaning procedures
 Regular maintenance of premises and plant
 Effective ventilation
 Ensuring compatibility between products and containers and use of suitable packaging materials
 Appropriate dress codes for staff
 Effective insect and pest control
 Effective label control
 Appropriate in‐process and final product quality control tests for residual starting materials, process materials, by‐products etc.

Question 72

The Pharmaceutical Manufacturer

Answer 72

The purchaser can increase assurance of quality by:
 Ensuring that the supplier appreciates the vendor’s quality requirements
 Auditing the supplier, assessing risk and agreeing appropriate procedures and quality control checks to be performed by the supplier
 If necessary, incorporating additional checks over and above pharmacopoeial requirements for contaminants into the testing schedule for the incoming material

Question 73

API Impurities and Common API Purification
Techniques

Answer 73

Important Processing/Purification Methods
Chemical conversions do not give 100% of the required product from the starting material. The API manufacturer therefore concentrates on the efficiency (in economic terms) of each synthetic process step. Unwanted by‐products and waste (e.g. used solvents) are removed to ensure maximum conversion at the next synthetic step, until the crude API is obtained. Subsequent processing is purification for the removal/reduction of impurities.
The techniques used to purify active pharmaceutical ingredients are many. While the primary thrust of the process is to remove chemical impurities, ancillary processes such as filtration will remove physical impurities and the aggressive reagents used will typically reduce bioburden. Most of the techniques fall into one, or more, of the following groups.
 Crystalisation, filtration, and isolation
 Decolourisation
 Precipitation
 Drying
 Distillation
 Evaporation
 Solvent extraction
 Chromatography
 Resolution of optical isomers

Filtration, Crystallisation and Isolation
1. Filtration of Product Solution
This is the traditional and most common way to purify solid products.
The crude product is dissolved in a suitable solvent. The preferred solvent is one in which impurities have good solubility and the target product (intermediate or API) has a solubility that rises rapidly with increase in
temperature.
The crude product is suspended in several volumes of the solvent and the temperature is raised to close to the boiling point to dissolve all of the solids. The hot solution is then filtered to a clean vessel and crystallised under
controlled conditions, ready for Isolation.

2. Crystallisation of the Filtered Solution
   The control of crystallising an API is vital to its final physical form, and therefore its bioavailability in its medicinal presentation. Lack of control can result in different crystal forms as is demonstrated below with calcium stearate. Various crystallisation techniques are used; depending upon the crystal form required:
    Natural cooling to a pre‐set temperature. The product crystallises as the temperature ‘drifts’ down over several hours
    Controlled crystallisation. A strict regime of agitation and temperature control are required either to obtain the correct crystal form and/or to minimise the occlusion of impurities in the products. The cooling is at a pre‐set rate and both the cooling rate and the agitation may be stepped
    Seeding. A product seed is added to the product solution at a pre‐determined temperature, so that crystallisation is grown out of the seed site
    Any combination of the above activities. Normally seeding is part of controlled crystallisation
    Specialist techniques, for example ultrasonic crystallisation Ritonavir was temporarily withdrawn from the market because a different polymorph (II needles) was causing the drug product to fail the dissolution test and it was precipitating out of capsules. Eventually chemists discovered that careful reflux control and crystallisation‐cooling‐cycle control were the key factors to ensuring the formation of the required polymorph (I – rods)
3. Isolation
   Isolation is the technique of separating the required product from its liquids after crystallisation.
   Ceramic Filter
   The solid API is harvested, that is, collected (isolated) on some type of filter or centrifuge. The quality of the product is very dependant upon the efficiency of the removal of the mother liquors, which are enriched
   with the impurities. (Sometimes these liquors are first removed by decantation.) With a manual ceramic type filter, this is effected by vacuum followed by displacement washes using the cold solvent.
   However both cake‐cracking and wash solvent channelling are potential difficulties, and the efficiency is dependant on operator technique. These difficulties also exist with product isolation on a centrifuge, but can more readily be overcome by mechanisation of the operations. Centrifugation is generally better than filtration giving a
   lower cake moisture and better washing capability. Centrifugation efficiency is greatly enhanced by automation of both feed rate and washing sequences. Increasingly these techniques are being replaced by the use of modern filtration vessels which use agitated washing sequences and generally are dual purpose ‐ they incorporate product
   drying.

Decolourisation
This technique is usually combined with the filtration and crystallisation technique outlined above; and is therefore followed by product isolation. The hot solution is treated with an inert substance, such as activated‐carbon, which absorbs the impurities (unwanted colours) giving a much improved solution and product colour. It is possible to select carbons that are particularly suited to polar or non‐polar solvents or that have low iron contents and are suited to acidic conditions.
In aqueous solutions it is often possible to remove colours chemically. Very often these colours are due to oxidation of the product or one of the impurities and in some cases due to combinations with trace metals, usually transition metals in higher oxidation states. Sodium Dithionite is often particularly effective in removing the latter type of discoloration, and is used in controlled amounts so that residual sulphur‐containing contaminants are minimised in the API product.

Precipitation
This technique replaces crystallisation in the above. An acid or alkali reagent is added to the hot solution of the product to give the required salt which precipitates because it is insoluble in the solvent. Complete precipitation is effected by cooling. A variation of this technique is to distil out the first solvent, replacing it by a second cold solvent in which the product is insoluble (the anti‐solvent) by controlled addition. Older techniques include in‐line precipitation (e.g. using a Venturi mixer). Modern methods of precipitation include supercritical fluid (SCF) precipitation and high gravity precipitation. The same controls as for crystallisation are employed for precipitation.

Product Drying
All solid forms of API material are dried after isolation of the solvent‐damp solid by one of the techniques mentioned earlier. There are a variety of driers available for such purposes. If tray‐driers are used, the batch of API
must be homogenised after drying. Lyophilisation, or freeze drying, is a specialised technique which exploits the physical properties of water. By freezing an aqueous solution, ice can be caused to sublime to water vapour
at low pressures, whilst supplying heat. It is used to prepare stable products from materials which are unstable in solution, even at low temperature. Such materials are heat‐sensitive and may be easily oxidised.

Distillation
Distillation is the partial evaporation of a mixture of liquids (product and impurities), and subsequent condensation to collect the desired component (product). This technique is normally used to purify volatile liquids but can be used for low boiling point solids. The distillation is usually carried out at normal or reduced pressure.
Occasionally it is performed at higher pressure for very volatile materials. The vapour from the boiling liquids is passed up a vertical tower. A condenser at the top allows condensate to flow back down the column (reflux). A take‐off valve or an automatic device, a reflux divider, is used to regulate the ratio of condensate returned to that
collected as fore‐run, product or tails. The column is filled with specially designed trays or packing materials to give a high surface area to allow good heat transfer between the vapour and condensate within the column. Materials of lower boiling point migrate towards the top of the column and can be removed as the fore‐run.
As this material is stripped off the column temperature gradually rises until the true boiling point of the wanted component is reached. By distillation monitoring tests, a point is reached when the product can then be allowed to pass from the column to the storage vessel. By adjusting the ratio of material removed to that allowed to flow back down the column (reflux ratio) the efficiency of separation can be adjusted.

For heat‐sensitive substances, short path distillation (molecular distillation) is used. It offers, by using
high vacuum:
 A low evaporation temperature
 Short residence time in the still

Evaporation
This technique is used instead of distillation for high boiling point liquids which are thermally stable. Elevated temperatures on the surface of the evaporator effect the separation of product from its impurities. A film distillation technique is normally employed ensuring that the product is not exposed to high temperatures for
prolonged periods of time. (Special thin film evaporators, wiped wall evaporators or short path distillers, can also be used to effect gentle thermal separations).

Solvent Extraction
Advantage can sometimes be taken of the difference in polarity between the wanted product and the impurities. The crude product could be suspended in a non‐polar solvent such as toluene. When heated the low polarity product will pass into solution and the more polar impurity can be removed by washing with water or aqueous acid or alkali as appropriate. The product can then be recovered from the toluene solution, following phase separation. The efficiency of this procedure is dependent upon the distinction of the interface between the organic and aqueous phases, and process parameters such as temperature and agitation. Solvent extraction can be run as a continuous process using centrifugal counter‐current extractors (e.g. extraction of penicillin V free acid).

Chromatography
This technique can also be used to separate mixtures of different chemical and/or physical properties or mixtures of polar and non‐polar materials. By passing the crude solution down a column packed with a stationary phase such as silica, alumina, an ion exchange resin, or a polar material, the target product can be held on the column and other materials, such as non‐polar colouring agents or other materials for which the column packing has no affinity, can be washed through to waste. The target product can then be recovered from the packing by use of a suitable solvent system. This recovery operation also often regenerates the packing for re‐use. This technique has been used very successfully to isolate natural materials from crude extracts. However, columns tend to lose efficiency due to channelling. This can allow significant volumes of the solution to by‐pass much of the column material. This can be remedied by using reverse flow. When solutions are pumped up the column, the flow tends to lift the resin bed slightly, allowing air pockets to flow upwards and out of the column. The turbulence generated also prevents semi‐permanent channels forming. Examples of chromatography techniques include:
 Ion Exchange Chromatography
 Chiral Chromatography
 Affinity Chromatography
 Hydrophobic Interaction Chromatography
 Mixed Mode Chromatography
 Size Exclusion Chromatography
 Reverse Phase Chromatography

Resolution of Isomers
When a pharmaceutically active material exhibits stereo‐isomerism, the activity and the side effects are usually unequally distributed between the forms. Regulatory agencies are now taking the view that if it can be demonstrated that the activity resides in one isomer and that the other contributes only to increasing the frequency and severity of the side effects, then the isomers should be separated. In cases where the unwanted isomer is toxic, it must be removed to a strictly controlled level. The desired isomer may be obtained either by selective synthesis, (either totally selective, or in an enriched form) by some type of stereo‐specific (chiral) synthesis, or by separating the racemic mixture. Stereo‐specific synthesis requires careful control of isomers. Separation of a racemic mixture means expensive product is being made unnecessarily, only to be discarded. Thus the preferred method is to use a starting material in which the chiral centre is already present, i.e. to synthesise only the desired enantiomer.

When separation is the only option, the classical approach has been chemical separation, or Resolution as it is usually known. This involves reacting the racemic mixture with one isomeric form of another optically active reagent. The two products resulting from this no longer behave in the same way and usually have different solubilities and can thus be separated. This process is often not very efficient and has to be repeated several times. Sometimes the residue rich in the unwanted isomer can be treated to cause it to revert to the 50/50 racemic mixture enabling recycling back into the process. The overall process is costly and will sharply increase the cost of manufacturing the required enantiomer. Another approach is to use chromatography techniques to separate racemic mixtures. Examples of pharmaceutically active materials that are sold in the active form are:
 Adrenaline (Epinephrine)
 Amphetamine
 L‐Dopa

Question 74

Facilities for APIs

Answer 74

Introduction
The various guidance documents on GMP for APIs are not particularly helpful when it comes to details of the design and construction of facilities e.g. EU GMP Guide, Part II/ICH Q7 GMP Guide for APIs
The one exception to this general rule is the ISPE Baseline Pharmaceutical Engineering Guide, Volume 1 Active Pharmaceutical Ingredients (Second Edition June 2007), which does provide very detailed and specific recommendations, particularly concerning:
 Architectural finishes (floors, walls, ceilings, etc.)
 HVAC design

Contamination and Cross‐Contamination
A major theme of the various GMP guidelines is avoidance of contamination. The mechanisms to achieve this, proposed by all of the guides include:
 Separation of critical activities and certain product categories
 Layout designed to give suitable:
 Materials and equipment flows
 Personnel access
 Maintenance access
 Finishes to allow adequate cleaning and attainment of required environmental standards
 Ventilation systems designed to provide product protection

Once again however it is only the ISPE API Baseline Guide which provides any detailed and specific
reference to the fact that the standards for the facility may vary depending on:
 The nature of the product:
 Early/late stage intermediates
 Pure/impure
 Sterile/non‐sterile
 The nature of the process:
 Closed/open
 Wet/dry

All the guidelines however make general reference to the gradually increasing implementation of GMP principles, and this is certainly the expectation for facilities, where the standards for the final stages of API manufacture should be essentially the same as for the first stage of dosage form production.

Question 75

API Separation of Products and Activities

Answer 75

Separate facilities are an absolute requirement for penicillins. Although various guides imply that it would be possible to manufacture other products in the same building, provided manufacturing and HVAC systems were dedicated, it is extremely unlikely that this would in fact be considered acceptable by any of the relevant authorities; even if it was, the burden of validation and monitoring would be so great as to make separate buildings a far more attractive option.

This situation is also now the norm for cephalosporin manufacture and this is acknowledged in all the recent API guidance. For example, the ICH Q7 Guide states: “Dedicated production areas, which can include facilities, air handling equipment, and/or process equipment, should be employed in the production of highly sensitising materials, such as penicillin and cephalosporins.”
It should be noted that the EU GMP Guide requires that facilities for the manufacture of medicines should not also be used for production of “technical poisons such as pesticides and herbicides”. This product mix is not unknown for API manufacturers, so the ICH Q7 Guide states:
“Any production activities (including weighing, milling, or packaging) of highly toxic nonpharmaceutical materials such as herbicides and pesticides should not be conducted using the buildings and/or equipment being used for the production of APIs. Handling and storage of these highly toxic non‐pharmaceutical materials should be separate from APIs.”

Other product categories where clear separation is required include:
 Cytotoxics
 Steroids and hormones
 Radio isotopes
 Narcotics (generally controlled by other mechanisms)
 Other potent or sensitising drugs

In these cases, the separation may be achieved by:
 Campaign working
 Procedural controls
 Use of validated cleaning procedures

Whenever these classes of product are handled, therefore, increased emphasis must be placed on:
 Development of validated cleaning procedures
 Implementation of systems and procedures to avoid the risk of mix‐up or contamination

In 2005 the EMA issued a concept paper outlining their intent to update EU GMP guidance related to ‘dedicated facilities’. Industry indicated that with modern science and risk‐based approaches and advances in technology it was no longer appropriate to mandate facility dedication for many of the product ‘groups’ proposed. For many of the ‘groups’ there is a wide range of molecules which may have different potencies – so a ‘one‐size fits all’ approach is not needed. Industry proposed a case by case risk‐based evaluation approach by the manufacturer. Subsequently, ISPE have published a guide on this topic (Risk‐MaPP).
It is hoped by industry that future guidance will permit a science and risk‐based approach as to whether to dedicate facilities, although certain products will still require dedication. Certain key process stages are identified or may be seen as requiring separate segregated facilities. These include:
 Receipt sampling and quarantine of raw materials
 Quarantine and sampling of intermediates and finished APIs
 Holding of rejected goods
 Storage of released materials
 Storage of packaging materials
 Ingredient weighing
 Manufacturing and processing operations
 Equipment washing
 Packaging operations
 Laboratory testing

The degree of separation and segregation for all of these activities will depend upon the nature of the materials being handled; however, a number of basic considerations should be observed:
 Allow sufficient space for activities, particularly maintenance and other non routine situations
 Do not use production areas and corridors for storage. Provide adequate storage space for work in process

Layout and Organisation
The paramount concern in designing a facility layout should be to provide a logical and orderly flow for:
 Personnel
 Materials
 Equipment (clean and dirty)
This does not necessarily mean a one‐way flow, although this is often highly desirable, as long as the requirement to avoid the risk of mix‐up or contamination is satisfied. Points to consider include:
 Separate routes for people and materials
 Personnel entry to controlled areas via suitable changing rooms:
 Controlled areas; single stage (air lock)
 Clean rooms; 2 or 3 stage
 Materials flow to follow the production sequence and avoid cross‐overs
 Working areas not to be rights of way
 Access for maintenance and equipment and routes to washing areas
 Protection from insects, birds, etc.
 API production equipment can be located outside provided a closed process is in use

Question 76

API facility finish and design

Answer 76

The design features and standard of finishes for an area should vary depending on the use to which the area will be put. The ISPE API Guide provides a useful table of recommended finishes for floors, walls, ceilings, etc. categorised by the level of protection required in the area. The terminology used by ISPE is however somewhat confusing and not always in agreement with that used in dosage form manufacturing – eg ISPE’s ‘general’ (Level I) area would more commonly be classified as non‐controlled (ie no positive ventilation), while ISPE’s ‘protected’ area (Level II) would be known as controlled (ie positive ventilation) and ISPE’s ‘controlled’ area (Level III) would be more commonly termed as classified (ie known particulate standard).

A simpler way of identifying appropriate standards is by the area’s function, ie
 Storage Areas
 Clean, dry, temperature and humidity monitored where appropriate
 May be outside
 Separate sampling area or means to control contamination
 E.g. down flow booth, local ventilation
 Highest standard finishes where material is exposed
 E.g. sampling
 General storage areas; non‐dusting, infrequent cleaning, exclusion of pests (e.g. curtain doors)
 Production Areas
 Smooth cleanable surfaces, free from cracks (where enclosed)
 Avoidance of difficult to clean areas and dust traps eg services:
 Particular problem for APIs
 Mainly closed processes at early stages
 Drains to be trapped
 Personnel changing/washing facilities
 Separate entry/exit for materials
 Effective ventilation
 Final Isolation and Packaging for Non‐Sterile APIs (Controlled not Classified)
 Highest quality of finishes and environment
 Cleanable, smooth coved walls, floors, ceilings
 Minimal dust traps, services enclosed
 Trapped drains only, capped
 Controlled access:
 Personnel changing facilities
 Air lock entry/exit for materials
 Positive ventilation at least EU8
 Sterile Processing
 Same standards as for dosage form manufacture
 Smooth, non‐shedding surfaces
 Coved walls, floors and ceilings
 No dust traps, flush fittings and glazing
 No drains
 Multi‐stage personnel changing facilities
 Controlled materials entry and exit, through sterilisers or using sanitisation process
 Class B clean room for aseptic production, C or D for low bioburden materials

Heating, Ventilation and Air Conditioning (HVAC)
The primary aim of HVAC in the manufacture of pharmaceutical products and APIs is to protect the product from the risk of contamination and cross‐contamination. The protection of personnel is a secondary consideration, which is in direct contrast to the chemical manufacturing industry where this is the main purpose of ventilation systems.
It follows that the type and direction of air flow is also typically different, normally providing a positive flow of filtered, clean air over the product, rather than an extract away from the product and operating personnel. This does not mean that these two objectives are mutually exclusive. In fact good design can invariably provide both product and operator protection and some examples of how this can be achieved will be presented. In the extreme case where product protection is required to maintain the sterility (or low bioburden) of a product, then a very high quality environment is required. This can only be achieved by the use of high efficiency particulate air (HEPA) filters and by the use of rigorous operating and control procedures.

Question 77

API facility Filtration and Environmental Standards

Answer 77

In broad terms, environments are typically classified as follows:
 Uncontrolled
 No filtered air supply; may also be termed ‘socially clean’ if appropriate standards of finishes and housekeeping are applied
 Controlled
 Provided with a filtered air supply
 Input air quality specified, but not the room environment
 Limited environmental monitoring carried out
 Typical situation for non‐sterile dosage form manufacture, using moderate efficiency filters (EU8) and 6‐12 air changes per hour (ac/h)
 Classified
 Room air quality is specified and monitored (typically against a defined standard eg ISO 14644, EU GMP Guide etc.)
 Required for sterile manufacture, increasingly common in ‘high risk’ non‐sterile dosage form manufacture eg liquids, creams and ointments
 HEPA filtration required at >20 ac/h

Filtration Standards
Historically many different approaches have been used to classify the effectiveness of air filters. The most widely used current standards are:
 EN779
EN779 is based on the earlier ASHRAE and Eurovent standards and classifies coarse and fine filters on the basis of dust spot efficiency. Filters with an initial dust spot efficiency below 20% are classified as arrestance filters (coarse filters) in the general range G1‐G4. Filters with an initial efficiency greater than 20% are classified as efficiency filters (fine filters) in the range F5‐F9. The classification is based on the use of a test dust with a size range around 2‐5 micron. The arrestance technique measures the dust uptake on a gravimetric basis, efficiency measurements are based on discolouration of the filter. These filters are typically used in generating controlled environments in the manufacture of non‐sterile pharmaceuticals and APIs.
 EN 1822 HEPA and ULPA Filters
This standard defines grades H10‐H14 and U15‐U17. This classification is based on penetration at the most penetrating particle size (MPPS), typically between 0.1‐0.2 microns of an aerosol challenge. As well as the overall classifications there are requirements for local penetration (typically a maximum of 5 times the overall limit value) for filters from H13 to U17. This standard replaces the old sodium flame test and is similar to DOP (dispersed oil
particulates) tests that may be carried out in‐situ. These filters are used to product classified environments.
 MERV Ratings
Minimum Efficiency Reporting Values (MERV ratings) are defined by ASHRAE Standard 52.2. This is based on testing of the filters by exposing them to a range of test particles between 0.3 and 10 microns in size and using a particle counter to measure the upstream challenge and the downstream penetration to determine filter efficiency values. MERV ratings of 1‐20 are then assigned based on the results of this testing. Filters are then put into 5 groups, rather in the same way that the European system uses G,F,H and U categories.
An approximate comparison of these filter classifications is given in the table in Annex 1.

Environmental Classifications
Although historically there have been many clean room standards used around the world, there are now only two (strictly speaking only one!) that we need to be aware of. These are:
 US Federal Standard 209
This standard no longer exists officially, as the US has now adopted ISO14644 (see below), but the terminology of the early versions (up to revision D) is still very widely used. Partly this is because this system is still referenced by the FDA in documents such as the 1987 aseptic processing guidelines, which have not been updated to reflect more current usage. Partly it is because the terminology is easy to use and understand.
The classifications in this system represent the number of particles, of 0.5 micron diameter or greater, per cubic foot of air.
Thus, for instance, Class 100 or Class 10,000 and Class 100,000 which are identified respectively as the requirements for critical or support zones in the FDA aseptic processing guidelines.
There was an attempt to ‘metricate’ this system (209E) by using the number of 0.5 micron particles per cubic metre of air and applying exponential notation. This led to some very strange categories e.g.
Class 100 equivalent to class M3.5
Class 100,000 equivalent to class M5.5 etc.
This usage was never widely adopted and FS209 has in any case now been replaced by the following:
 ISO 14644
This standard is based on a Japanese (JACA 24) standard. It is very flexible and allows classification on the basis of any particle size from 0.1 to 5 microns.

Application of Environmental Classifications to Pharmaceutical Manufacture
In the EU GMP standards (Grades A‐D) limits are given for both the at rest and in‐operation conditions, so there is no ambiguity. Where FDA state requirements for clean room standards, however, they refer only to the ‘in‐operation’ state and this should be recognised when comparing EU and US requirements.
The actual equivalencies are:
EU Grade A: Class 100 (ISO5) both at rest and in operation, plus microbial limit of less than 1
cfu/m3
EU Grade B: Class 10,000 (ISO7) in operation, plus max 10 cfu/m3
EU Grade C: Class 100,000 (ISO8) in operation plus max 100 cfu/m3
EU Grade D: No direct equivalent, only classified ‘at rest’ max 200 cfu/m3

Air Flow Philosophies
Given that the primary aim of an HVAC system in pharmaceutical manufacturing is the protection of product, the simplest way to achieve this is to provide a flow of filtered air over the exposed product.
The air could then be either:
 Allowed to dissipate
 Extracted and vented to waste
 Extracted and recirculated (after appropriate refiltration)

Air Flow Philosophy
 Provide product protection
The first issue to consider is whether recirculation is desirable or possible. Several factors must be considered to assess the risk of contamination from recirculated air:
 The nature of the materials being handled eg biological activity, other hazards, dilution
 The level of contamination possible, where dry products present greatest risk
 The operating procedures and systems in use
The simple air supply philosophy identified earlier is however often complicated by other factors such as:
 Several areas being served from the same air handling unit (AHU)
 Different activities taking place in adjacent areas
 Transport of materials and equipment through common areas
In such cases there are two major variants in the design of air flows.
With this approach, as previously, clean air (fresh or recirculated) is supplied over the exposed product.
The problem however is that dust from the work area may be entrained and find its way into adjacent work rooms via the common corridor through turbulent flow or contamination of common equipment, personnel etc. Therefore for dry products the arrangement generally favoured is the clean corridor.
This provides greater containment of any dust generated in the working rooms. The major problem is if dusty product or equipment is moved through the corridor, when contamination may result.
Therefore, this practice must be avoided.
These arrangements may be further complicated however when handling sterile materials, where product protection cannot be compromised in any way. In this case the normal arrangement is as shown in Figure 2, but where containment is also required; perhaps because of toxicity or other concerns, this can usually be achieved by the use of positive or negative pressure air locks.

Localised Environmental Control
Local extraction ventilation (LEV) systems can be used to prevent ‘fall‐out’ but are only effective up to 30cm. There is no recirculation of air. Control of contamination is via filter changing regimes. Other mini‐environments which are very useful to protect vessel openings or product‐discharge operations are laminar flow hoods (LAFs) or cabinets. These are very much like isolators and provide clean controlled and/or classified environments for product handling activities. Increasingly continuous bagging systems are being employed for hazardous materials. These can be used in uncontrolled environments.

Ventilation Standards for APIs
There is little official guidance in this respect. The FDA have commented that for APIs (Guide to Inspections, 1991/94) recirculation of air through an ‘85% efficiency’ filter may be adequate for a single product facility or for handling of damp materials, but for a facility handling multiple dry powder products, ‘even HEPA filtration may not be adequate’ (ie single pass air is required). The more recent draft FDA ‘Guidance for Industry’ document refers only to air filtration systems that are ‘appropriate’.
The most definitive source of guidance for air filtration standards for APIs is the ISPE API Baseline
Guide. This defines three levels of protection:
 Level I, General: no exposure (closed processes) or minimal exposure for non‐critical activities, e.g. charging materials or sampling of an early stage intermediate. No product protection required, use G4/MERV 8 filters
 Level II, Protected: minimal exposure for critical operations or full exposure for non‐critical activities, e.g. open handling of intermediate material, charging seed crystal to final product in vessel. Use minimum F7/MERV 13 filters, but HEPA filtration required if air is recirculated from a multi product facility
 Level III, Controlled: exposed, critical operations, e.g. final product handling. Ventilation standards as above

These recommendations do not make a clear distinction between Level II and Level III requirements.
Other factors, such as the intended use of the product (eg for use in a sterile or oral dosage form) would need to be considered here, although this is not specifically addressed by the ISPE Guide. There is no specific guidance either for handling of sterile APIs, but in this case the requirements for dosage form manufacture would equally apply. In general though, these proposals are in reasonable agreement with the long standing expectations of the FDA and the UK MHRA for processing of nonsterile dosage forms, where F7 or better filtration with around 6‐12 air changes/hour would be regarded as a minimum standard, for the final processing stages of non sterile APIs. The use of HEPA filters, or even classified environments, for these activities has in fact become typical industry practice, reflecting the expectations of both the ISPE guidance and the FDA as noted earlier.
Similarly the lower standard of filtration suggested (equivalent to G4) with 6‐10 ac/h would be regarded as generally acceptable for area ventilation where product is minimally exposed or for early stages of API manufacture. Again it should be noted that this is a minimum standard and higher standards or local protection may be required in certain situations.

Question 78

GMP Utilities Used in AS Manufacturing Including Water, Gases and Effluent Removal/Treatment

Answer 78

Introduction
Water is used extensively in the AS Industry. However, it is only one of a number of critical utilities
employed in an AS plant during chemical processing. Others include:
 Steam
 Compressed gases
 Gaseous effluent venting systems
 Effluent drainage systems
 Vacuum systems
 Coolant fluid systems
 Heating fluid systems
Bulk supplies of raw material reagents, such as bulk solvents, acids and alkalis, are sometimes also classed as utilities.

Water
Water is used:
 As a solvent in chemical processes
 As a diluent in the preparation of chemical reagents
 For cleaning plant and equipment
 In laboratory reagent preparations

Grades of Water
The selection of water type will depend upon:
 The product being manufactured (fine chemical, intermediate or AS)
 The processes involved
 The intended use of the water (cleaning or processing)

The EMEA’s CPMP Quality Working Party (QWP) first published its ‘Note for Guidance on Quality of Water for Pharmaceutical Use’ in June 2002. The guidance was updated in 2020 to reflect the following changes in the
European Pharmacopoeia:
 Revised monograph for Water for Injections allowing the possibility to use methods other than distillation for producing water of injectable quality;
 New monograph for Water for preparation of extracts,
 Suppression of the monograph for Water, highly purified.
The guideline has also been updated to reflect current expectations for the minimum acceptable quality of water used in the manufacture of active substances and medicinal products for human and veterinary use.
That note, contains comprehensive guidance (from an EU perspective) on water types and appropriate uses. Tables 3 and 5 describe the grades of water required for AS processes and cleaning operations.
EudraLex Vol 4 Part II Section 4.3 states that AS process water should at least be potable water quality. It should meet WHO standard.

Quality Requirements
 Controlled by national legislation
 Emphasis on suitability for drinking
 Strict control over gut bacteria
 Chlorinated to prevent microbial growth?
 Pharmacopoeial Guidance?
USP: 500 cfu/ml
Other Water Grades
In addition to those grades of process water described earlier, other ‘unofficial’ grades are commonly
used. For example…
 Potable Water with Microbiological Control
 Used especially in final AS crystallisation steps
 Potable Water with Microbiological and Endotoxin Control
 Used in final stages of AS for parenteral use
 Purified Water with Low Bioburden/Endotoxin
 Used for final rinsing of chemical reactors following clean‐out procedures and in the final stages of AS for parenteral use

Summary of Water Uses
Final isolation and purification of Sterile AS : WFI
Purification where AS is non‐sterile but intended : Purified Water with microbial and to be used in a parenteral formulation endotoxin control
AS for use in non‐parenteral sterile products : Purified
AS synthesis : Potable (minimum)
Initial equipment cleaning : Potable
Final equipment rinsing : Same quality of water as used in the AS manufacture

Question 79

Production and Distribution of Purified and Water for Injections

Answer 79

In order to achieve the required water quality (chemical, physical and biological) a combination of treatment processes is likely to be necessary.
Typically this may include:
 Chlorination
 Active carbon treatment
 Filtration
 Softening
 Deionisation
 Ultrafiltration
 Reverse osmosis
 Ozone or ultra violet sanitisation
 Distillation
 Distribution system
Each of these processes has a particular function and may be required in specific circumstances i.e.:
 Chlorination: To reduce bioburden
 Active carbon treatment: To remove organic impurities and residual chlorine

Essential Message: Once the chlorine has been removed, microbial proliferation is the greatest concern.
 Carbon beds require frequent cleaning (back flushing) to remove nutrients.
 Filtration: To remove particulates in feed water and also from the treatment processes, e.g. active carbon fines, fragments from resin beds
 Filters should not be seen as a way to reduce or eliminate microbial contamination.
They will rapidly become colonised and ‘grow through’ will occur.
* Softening: May be desirable depending on water usage and feed water quality
* Reverse osmosis: Most effective at removing large molecules, but depending on input water quality may produce water meeting Purified Water requirements. System operation is complex and output water quality will depend on whether single or multi‐pass systems are used and in the take off ratio employed. Frequent chemical sanitisation is necessary to prevent bio‐film build up
* Deionisation: The most widely used chemical purification method. Conventional systems may be twin or mixed beds of anion and cation exchange resins, continuous (electrolytic) deionisation systems are now more widely used

Essential Message: Deioniser resin beds provide an excellent nutrient source for microbial growth.
Frequent regeneration is essential to control this. Do not over size the system. Where mixed beds are regenerated off‐site and replaced, ensure that this is done under clean conditions and regenerated beds are stored under alcohol/water.
Deionised water will almost certainly meet the chemical quality requirements for purified water without further treatment.
 Ultrafiltration: may be useful in removing high molecular weight contaminants such as pyrogens
 Ozone or ultra violet sanitisation: ozone may be injected into the purified water as a very effective sanitising agent. Excess can then be destroyed (leaving no residues) by UV irradiation.
Such systems are expensive, however, and are comparatively rare in the pharmaceutical industry
Much more widespread is the use of UV irradiation alone, typically on the return loop to the purified water storage tank.

Essential Message: UV may not kill all microorganisms, but may lead to some becoming damaged and therefore slow to grow (if they recover at all) under the conditions normally employed for water testing.
Low nutrient media (e.g. R2A) and suitable conditions for incubation (25oC, 7‐14 days) may be necessary to demonstrate the presence of such organisms – they may well recover and grow in your product!
 Distillation: the only universally accepted method of preparation for wfi. Multi effect stills are normally preferred, especially to reduce the risk of carryover of pyrogens in water droplets
 Distribution: a critical part of the system. Constant recirculation is essential for wfi and usually employed for purified water – if not water should be prepared on demand only and not stored Plastics such as PVC or ABS may be used for room temperature distribution of purified water but are prone to colonisation (particularly at solvent welded joints). Stainless steel (normally 316L) is most widely used for ‘hot’ wfi systems (EC requirements: above 70oC, US requirements: above 80oC) but pipe surfaces around welds may be a source of “rougeing” if passivation is not employed at appropriate intervals.
PVDF is being promoted as an alternative which is already in use in the electronics industry. For all wfi systems quality of welds, fittings and surface finish is critical. Dead legs should be avoided and these are variously defined as 6x, 4x or 2.5x the pipe diameter by different authorities or suppliers. The trend is towards use of zero dead leg fittings and valves.
Occasional testing for thermophiles is desirable in hot systems.
Sampling ports should be provided at key points (e.g. before and after each process stage) both for validation and routine monitoring purposes.

Question 80

API other utilities

Answer 80

General Requirements
ICH Q7 Section 4.20 focuses on all utilities which could impact on product quality (ISPE define these as ‘direct’ impact systems).
The general requirement is that these utilities are adequately qualified and appropriately monitored.
Corrective actions must be taken if any defined limits are exceeded. There should be a full description of these utility systems in engineering drawings.

Steam
Plant or Boiler steam is mainly used as a heating fluid. Sometimes it can be used with care for sanitisation or sterilisation purposes but not for direct product contact. The GMP items of concern are:
 The additives used to soften the water and to prevent boiler corrosion
 The adequacy of the distribution pipework (materials of construction and joints)

Clean Steam
Special clean steam generators supplied via welded stainless distribution systems are required for product contact situatons, e.g. steam distillation processes and the sterilisation of product contact surfaces, usually sterilise‐in‐place (SIP) for sterile AS production. The requirement is that high quality condensate should:
 Meet pharmacopoeal standards for chemical purity
 Be sterile and pyrogen free
The quality of steam for sterilisation requirements are:
 Saturated (phase boundary) steam
 Dryness fraction 0.95 – 1.05
 NMT 3.5% non‐condensable gases

Compressed Gases
Nitrogen gas is widely used in the AS industry to provide an intert atmosphere, which is necessary for the safe processing of chemical reactions. It is also used to convey liquids and solids ‘by pressure’.
Argon is sometimes used for specialised processsing, especially if the reaction or product is very sensitive to moisture. Air or Carbon Dioxide may be used for product conveyance.
Compressed gases are either prepared from on‐site air‐liquifaction plants or obtained from commercial sources and stored as liquids in on‐site storage tanks or bottles. Oil free compressors are required in these plants. Moisture is avoided by drying the gas below the dew point (‐40°C) and Oxygen content (NMT 10 ppm) is controlled via a calibrated Oxygen meter. Supplier qualification (by audit) is an integral part of any IQ study.
Compressed gases are distributed through stainless steel or copper pipework. There should be inline filtrations from the storage to the pipework (1‐5, or 0.22 for low bioburden, filters are recommended). All pipework should be adequately identified (ICH Q7 Section 4.23).
All compressed gases systems should be qualified (DQ,IQ,OQ). It is particulary important to install non‐return valves and have suitable pressure‐reduction networks from plant mains to prevent contamination by back‐pressure or contaminations via common connections.
Generally routine monitoring (PQ) is by on‐line oxygen meters and moisture meters. These meters should be included in the calibration system.

Vacuum Systems
Dedicated reactor‐train vacuum systems are usually qualified as an integral part of the reactor‐train DQ, IQ, OQ studies. Common house vacuum systems should be subject to the systems qualifications required by ICH Q7 Section 4.20. These installations must include liquid catchpots (or spring‐leaf valves) to minimise contamination potential via common vacuum mains or manifolds, due to back flow (suck‐back). Operating process pressure ranges and entrained product issues should also be addressed.

Vent Systems
Gaseous effluent or exhaust vapours (‘off‐gases’) are collected through reactor vent systems. After scrubbing to remove objectionable gases, the effluent is either discharged to atmosphere via carbon bed filters or incinerated.
All vent systems should be appropriately qualified by DQ, IQ, OQ studies. This is especially necessary on multi‐purpose AS manufacturing plant, where cross contamination potentials, from backflow in both normal and abnormal processing conditions, via the vent mains must be minimised (e.g. use of non‐return valves, etc.).
Emergency vent systems need not be qualified. If pressure relief valves and devices are exceeded during processing, the integrity of the batch must be treated as compromised.

Question 81

API drainage systems

Answer 81

Liquid effluent systems should be appropriately qualified. The requirement of ICH Q7 Section 4.24 that ‘drains should be of adequate size and should be provided with an air break or a suitable device to prevent back‐siphonage’ must be addressed in the qualification study.

ICH Q7 Section 4.6: Sewage and Refuse
This section states that the GMP requirements for items such as sewage, refuse and waste, are their safe, timely and sanitary disposal. All containers and/or pipes should be clearly identified. Generally, in AS manufacturing:
 Waste solids are isolated from process streams and placed in containers for later disposal
 Liquids are removed via drainage systems, if they are compatible with water or aqueous in nature
 Gaseous by‐products are removed via vent systems

Question 82

Bulk Storage of Raw Materials, Solvents and Reagents
Each bulk storage system must be appropriately qualified. Special attention must be given to:

Answer 82

 Pipework: material identification and direction of flow labelling
 Loading and sample points (at tank or at point of use)
 Any common manifolds for solvents
 Suitable QC‐regimes for the mixing of new deliveries with existing quantities of stored materials in the bulk tanks
 Ongoing maintenance and monitoring

Question 83

GMPs and Quality Assurance for Excipients

Answer 83

Introduction
Excipients often constitute a major part of the composition of a dosage form. They can also, via their functionality, have a significant impact upon the performance of the drug product formulation – both in its manufacturing process and in the characteristics of the final drug product in use.
However, traditionally the profile afforded to excipients has been much lower than that afforded to the Active Substance (AS) with which they are combined.
Excipients are used for a range of reasons:
 To aid processing
 To provide functionality to effect stability, bioavailability, patient acceptability
 For product identification
People often refer to the ‘Excipients Industry’. In practice, there are few companies who specialise totally in pharmaceutical excipient manufacture, with many excipients being essentially commodity products, supplied for different uses to a range of customers across different industries. Often the offtake for the pharmaceutical market is quite small and hence brokers/agents are common in the supply chain – this can often make it more difficult to contact the original manufacturer.
Over 1200 excipients are used in marketed products (not including colours and flavours) with approximately 30% having standards in Pharmacopoeial monographs.
Sources of excipients and the complexity of their manufacturing processes have great diversity:
 Oil (as a starting point for many syntheses)
 Agriculture – maize, wheat, potato, sugar beet, etc. to give starches, dextrins, cyclodextrins, sucrose, sorbitol, etc.
 Minerals – talc, kaolin, sodium chloride
 Animals – lactose, gelatin
Considering cellulose:
 Total annual production 250 million tonnes
 Pharmaceutical use 50,000 tonnes = 0.02%
So a challenge to seek pharmaceutical standards?
But are the normal standards acceptable?
Excipients play a different role in a drug product than the AS, which provides the therapeutic effect.
However, whilst excipients are inactive, they may have a critical effect on how the formulation behaves and may need to be manufactured to meet specific dosage form needs (e.g. sterile excipients).
Historically, there has been self‐regulation of the standards for excipient manufacture and supply.

Question 84

API PRE-AUDIT QUESTIONNAIRE

Answer 84

Enables the auditor to focus the audit and target specific areas of concern.
The auditor may gather information on:
 Size and age of the facility
 Other products produced
 Complaints
 Regulatory review history
 Deviations (your products and all products)
 Key performance indicator history – e.g. deliveries on time
 Quality history

Question 85

API Audit prep

Answer 85

BACKGROUND INFORMATION
 Regulatory inspection history and frequency
 Site refurbishment and redevelopment plans
 Segregation of highly sensitising materials
 Customer complaints, recalls
Work sub-contracted out
 Off site operations

OTHER INFORMATION WILL GUIDE THE AUDITOR
TO AREAS OF POTENTIAL RISK
 Floor layout plans
 Flow of material
 Flow of people
 Organisation structure
 Staff turnover
 Area zoning or classification
 List of SOPs

POINTS TO CONSIDER WHEN
SCHEDULING
 Clearly state the objectives and agree agenda
 Agree if daily updates are required
 Time to call for documents – what to ask for
 Remember tours take longer than you think
 Remember you have to READ the documents you ask for!
 Always have a back-up plan if documents not ready
 Put some flexi time in the agenda each day

Question 86

API Audit

Answer 86

THE PROCESS FLOW
The most common audit is to follow the flow of the material through the process:
 Enables the operation to be reviewed sequentially so the impact of each stage on the next can be followed and assessed
 Confusion is usually avoided
 Risks caused by associated and neighbouring operations can be taken in context of the next stages in process
When may this NOT be the best process?

PLANT AND FACILITY RISKS
The auditor can assess risks during the tour. The tour is a very important part of the audit.
 An assessment of the facility/maintenance
 Verifying the accuracy of data recording
 Timely completion of records
 Calibration of equipment
 Adherence to SOPs

AT ALL TIMES ON THE TOUR
THE AUDITOR IS USING ALL
THE SENSES TO CONSIDER:
 Structure and fabric of the facility
 Cleanliness
 Cross-contamination risks (strong smells or highly indicative smells, e.g. penicillin)
 Labelling and identification
 Live examples of log book and documentation completion
 Condition of key equipment
 Knowledge of operational staff

ASKING THE QUESTIONS…
 Does it look loved and cared for?
 At all times is the identification and status clear?
 Does it feel logical and easy to follow?
 Do the operators look well presented, remember: If it is like this during an audit, what is it like normally!

ALSO, DURING THE TOUR THE AUDITOR IS
WATCHING AND OBSERVING THOSE AROUND…
 What do they want to show you?
 What don’t they want to show you?
 When do they exchange nervous glances or appear unusually relaxed and blasé?
 When do the auditor’s questions provoke an unusually strong reaction?

THE TOUR ALSO PROVIDES QUESTIONS AND
INFORMATION TO BE FOLLOWED UP LATER
 Rejected lots of raw materials found in the warehouse to check deviation or OOS systems
 Unusual events in room logs to check planned and unplanned changes
 Cleaning noted in log books – check cleaning validation and procedures support actual practices (between batch cleaning, between cleaning)
 Modifications and impromptu short term changes to key equipment – change control – validation?
 Training records of persons met on the tour

What is the process flow?
* Impact of each stage?
* Critical control points?
* What is the risk and how is it addressed?
* How does information flow from one department to the next?

General QA systems
 Area classification confirmation tests and results
 Environmental sampling points and results
 Water and other utilities
 Validation
 Calibration
 Deviations
 Quality investigation
 Out of specification
 Customer complaints
 Change control
 SOP control

Question 87

Desired API should be:

Answer 87

Ideally want API to be highly permeable and highly soluble.

Solubility enhances better to work with than permeability enhances

Needles are bad as cause poor flow

Question 88

API process

Answer 88

Solvents, reagents, raw materials make up the active substance starting material
API is processed to intermediate to make crude PI
Crude is purified
Followed by the crystallisation step
Filtration
Drying
Particle size reduction
Packing

Some stages may be combined. Solvents and raw materials are used throughout multiple stages. Some stages may be conducted at different locations. Not all stages are relevant to all APIs

Question 89

Certificates of suitability

Answer 89

Used where an ingredient manufacturer can provide evidence to show that the relevant monograph of the European Pharmacopeia can adequately control the quality of the ingredient

Question 90

Directive 2004/27 amended 2001/83 and Directive 2004/28 amended 2001/82 and these amendments were implemented into national law by 30 October 2005. They required:

Answer 90

• The active substances used to manufacture medicinal products to be made in accordance with GMP
  
  • A guide to GMP for active ingredient manufacture is required. This was originally issued as Annex 18 to the EU GMP Guide in July 2001, and is essentially the ICH Q7 guideline. The EU GMP Guide was revised so that; the existing Chapters 1 through 9 have become Part 1 for medicinal products and the GMP for APIs will become Part 2 (Annex 18 was removed)
  • Producers to be required to observe appropriate GMP
  • Regulatory authorities may inspect producers
  • A GMP certificate to be issued by “Competent Authorities” at the request of producers
  • A Community database of active ingredient producers be set up through EMA. This will include companies that have been given a GMP Certificate and companies that have been refused a GMP Certificate
  • Community pharmaceutical manufacturers to only use active ingredients from inspected, certificated producers
  • Repackaging and relabelling, for instance by a broker, is also covered
  • For APIs the GMP Certificate referred to will not be the equivalent of the Manufacturing Authorisation for Medicinal Products and there is not a requirement for a Qualified Person

Question 91

EU REGULATION 1252/2014

Answer 91

• Published 25 November 2014
  
  • Effective 25 May 2015
  • Provides legal basis for EU GMP Part II (ICH Q7)
    Subjects of Articles 3 to 18 of the Regulation correspond to sections 2 to 17 of ICH Q7

Question 92

QP API DECLARATION

Answer 92

• QP of MA applicant must declare:
  
  • APIs manufactured in compliance with GMP
  • Declaration also required for API Variations to existing MAs
  • Extended to cover GDP and supply chain in 2014

Question 93

THE QP API DECLARATION TEMPLATE

Answer 93

• Objective of this QP Declaration Template is to:
  
  • Emphasise the importance of providing a comprehensive declaration
  • To harmonise the format for the declaration
  • To forestall questions during assessment
  • To enhance the efficiency of the regulatory process
    Guidance on completion available on EMA website

Question 94

THE QP API DECLARATION TEMPLATE QP of MIA Holder should:

Answer 94

• Verify the GMP compliance for each registered API site, even if site is not routinely used
  
  • Verification should include an on‐site audit by suitably trained and experienced person(s), who may be a third party contractor
  • Define and fully understand the supply chain and verify the API supply chain
  • Ensure that appropriate technical arrangements are in place with any third party audit companies

Question 95

The QP API declaration template The template is divided into five parts:

Answer 95

Part A: ‘Concerned API Manufacturing Sites’, requires the QP to list and attest the full name and address of all API manufacturing sites and the manufacturing activity conducted at each site.

Part B: ‘Manufacturing/Importer Authorisation Holder(s) (MIAHs) to which this QP declaration applies’, requires the QP to list the MIAH(s) that use the APIs referred to in Part A.

Part C: ‘Basis of QP Declaration of GMP Compliance’, the QP to tick to confirm that an on‐site audit of the API manufacturer has occurred, then complete a table listing:
* The MIAH site (or contract giver)
* The auditing body (contract acceptor)
* The site audited
* The date of the last audit

If the date of the last audit is more than three years ago this has to be justified. There is also an optional ‘supplementary supportive information’ section.

Part D: ‘QP declaration of GMP compliance’ requires the QP to declare that:
QP Responsibility
* I am a QP with responsibility for GMP compliance of the active substance manufactured at the sites listed in Part A and am authorised to make this declaration
* The audit report(s) and all the other documentation relating to this declaration of GMP compliance of the active substance manufacturer(s) will be made available for inspection by the competent authorities, if requested
GMP Compliance
* The manufacture of the named active substance at sites given in Part A, is in accordance with the detailed guideline on good manufacturing practice for active substances used as starting materials as required by Article 46(f) of Directive 2001/83/EC and Article 50(f) of Directive 2001/82/EC
* This is based upon an audit of the active substance manufacturer(s)
* The outcome of the audit confirms that the manufacturing complies with the principles and guidelines of good manufacturing practice
Audit
* In the case of third party audit(s), I have evaluated each of the named contract acceptor(s) given in Part C and that technical contractual arrangements are in place and that any measures taken by the contract giver(s) are documented, e.g. signed undertakings by the auditor(s)
* In all cases, the audit(s) was/were conducted by properly qualified and trained staff, in accordance with approved procedures

Part E: ‘Name and Signature of QP responsible for this Declaration’, requires the QP to give their name and sign the declaration and provide their MIAH site and number.