ICH Q7 Guideline: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
`
`Q7 Implementation Working Group
`
`Questions and Answers
`
`Current version
`
`dated 10 June 2015
`
`International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
`
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`Dated: 10 June 2015
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`Q7 Q&As
`
`In order to facilitate the implementation of the Q7 Guidelines,
`the ICH Experts have developed a series of Q&As:
`
`Q7 Q&As
`
`Document History
`
`Q7 Q&As
`Approval by the ICH Steering Committee under Step 4
`10 June 2015
`
`References
`
`These documents are published at www.ich.org.
`
`ICH E2E
`ICH Q1A(R2)
`ICH Q5A
`
`ICH QSB
`
`ICH QSD
`
`ICH Q6B
`ICH Q7
`ICH Q8(R2)
`
`ICH Q9
`ICH Q10
`ICH Q-IWG
`ICH Q11
`
`Pharmacovigilance Plarming
`Stability testing of new drug substance and products February 2003
`Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived
`from Cell Lines of Human or Animal Origin
`Quality of biotechnological products: Analysis of the construct in cells used for the production
`of r-DNA derived protein products
`Quality of Biotechnological Products: Derivation and Characterisation of Cell Substrates
`Used for Production of Biotechnological/Biological Products
`Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products
`Good Manufacturing Practice of APIs
`Pharmaceutical Development
`Part I: ‘Pharmaceutical Development’
`Part II: ‘Annex to Pharmaceutical Development’,
`Quality Risk Management and the ICH Q9 Briefing pack
`Pharmaceutical Quality Systems
`Training Programme for ICH Q8/Q9/Q10
`Development and Manufacturing of Active Pharmaceutical Ingredients
`
`November 2004
`
`September 1999
`
`November 2005
`
`July 1997
`March 1999
`November 2000
`August 2009
`November 2006
`November 2008
`November 2005
`June 2008
`November 2010
`May 2012
`
`Legal Notice: This document is protected by copyright and may be used, reproduced, incorporated into other works‘, adapted, modified, translated or distributed under a public license
`provided that ICH’s copyright in the document is acknowledged at all times. In case ofany adaption, modification or translation of the document, reasonable steps must be taken to
`clearly label, demarcate or otherwise identifiz that changes were made to or based on the original document. Any impression that the adaption, modification or translation of the
`original document is endorsed or sponsored by the ICH must be avoided.
`The document is provided "as is" without warranty of any kind. In no event shall the ICH or the authors of the original document be liable for any claim, damages or other liability
`arisingfrom the use of the document.
`The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the copyright vests in a third party, permission for reproduction
`
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`Dated: 10 June 2015
`
`Q7 Q&As
`
`Table of Contents
`
`PREFACE ............................................................................................................................................................................................................................ .. 1
`
`1.
`
`2.
`3.
`
`4.
`
`5.
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`18.
`
`19.
`
`20.
`
`21.
`
`INTRODUCTION - SCOPE ................................................................................................................................................................................... ..2
`
`QUALITY MANAGEMENT .................................................................................................................................................................................. .. 2
`PERSONNEL............................................................................................................................................................................................................ ..3
`
`BUILDINGS AND FACILITIES — CONTAINMENT ......................................................................................................................................... ..4
`
`PROCESS EQUIPMENT — CLEANING .............................................................................................................................................................. ..5
`DOCUMENTATION AND RECORDS ................................................................................................................................................................. ..6
`
`MATERIALS MANAGEMENT ............................................................................................................................................................................. ..7
`
`PRODUCTION AND IN-PROCESS CONTROLS............................................................................................................................................... ..8
`
`PACKAGING AND IDENTIFICATION LABELLING OF APIS AND INTERMEDIATES......................................................................... ..8
`
`STORAGE AND DISTRIBUTION ........................................................................................................................................................................ ..8
`
`LABORATORY CONTROLS ................................................................................................................................................................................ ..9
`
`VALIDATION .......................................................................................................................................................................................................... 1 1
`
`CHANGE CONTROL ............................................................................................................................................................................................. 11
`
`REJECTION AND REUSE OF MATERIALS ..................................................................................................................................................... 12
`
`COMPLAINTS AND RECALLS ........................................................................................................................................................................... 12
`
`CONTRACT MANUFACTURERS (INCLUDING LABORATORIES) ........................................................................................................... 13
`
`AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS ..................................................................... 14
`SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL CULTURE/FERMENTATION........................................................... 15
`
`APIS FOR USE IN CLINICAL TRIALS .............................................................................................................................................................. 15
`
`GLOSSARY .............................................................................................................................................................................................................. 16
`
`ANNEX: Q&AS LINKED TO THE RESPECTIVE SECTIONS OF ICH Q7 .................................................................................................. 17
`
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`Dated: 10 June 2015
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`Q7 Q&As
`
`PREFACE
`
`Since the ICH Q7 Guidance was finalised, experience with implementing the guidance worldwide has given rise to requests for clarification of uncertainties due
`to the interpretation of certain sections. This Question and Answer (Q&A) document is intended to respond to those requests.
`
`The ICH Q7 document should be read in its entirety regardless of the nature of the manufacturing activities being conducted to fully understand the linkages
`between certain sections and successfully implement appropriate Good Manufacturing practices (GMPs) at all stages of the Active Pharmaceutical Ingredients
`(API) supply chain, including distribution. A table is provided as an Annex of this document showing the link between each Q&A and the relevant Sections of
`ICH Q7 and other ICH Quality guidance.
`
`ICH would like to acknowledge the work undertaken by the Pharmaceutical Inspection Co-operation Scheme (PIC/S). PIC/S contributed to this document by
`selecting and reviewing relevant Q&As that had been collected from training sessions since the implementation of Q7 and transferred the output of these reviews
`to the ICH Q7 IWG for consideration and consolidation, as appropriate. Additional questions were developed based on responses fi'om an ICH survey. PIC/S
`fi1rther contributed to the development of the document as an ICH Interested Party.
`
`Please note that ICH Q7 should be applied in combination with the principles laid down for development and manufacturing in ICH Qll (see definition of API
`starting material; see also ICH Q8(R2) Part II), Quality Risk Management (ICH Q9), and Pharmaceutical Quality Systems (ICH Q10). GMP principles as
`described in ICH Q7 should be applied regardless which approach is taken in pharmaceutical development and manufacturing.
`
`ICH Q7 also describes principles of GMPs to be applied in the manufacture of APIs for use in clinical trials (Section 19) and for APIs manufactured by cell
`culture/ferrnentation (Section 18).
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`INTRODUCTION - SCOPE
`
`Dated: 10 June 2015
`
`Q7 Q&As
`
`
`
`
`Does ICH Q7 apply to manufacturing
`Steps for the addition of substance(s)
`to an API (e.g., to stabilise the API)?
`
`
`
`When a mixture is classified in the regulatory filing as an API in a region or country in which it is used
`in a drug product, ICH Q7 should be applied to the manufacturing of these mixtures [ICH Q7, Section
`1.2, 20 — see Glossary for definition of ‘API’].
`
`QUALITY MANAGEMENT
`
`June 2015
`
`What is meant by ‘quality unit(s)
`independent from production’?
`
`The intent of the term ‘independent’ is to prevent any conflict of interest and ensure unbiased decision-
`making regarding quality-related decisions in the organisation structure. The person in the quality unit
`who is responsible for
`final decision-making (e.g., batch release decision) should not have
`res onsibilities for roduction activities ICH 7, Section 2.13 .
`
`Does ICH Q7 expect that the quality
`unit performs API release testing?
`
`While the quality unit has responsibility for the release of the API, which includes oversight of the
`testing and results, ICH Q7 does not prescribe specifically who performs testing.
`‘quality control’ in
`the ICH Q7 Glossary [ICH Q7, Section 20] refers to the activities, not the organisational structure.
`
`June 2015
`
`For examples of quality responsibility related to testing and release, refer to [ICH Q7, Sections 2.13,
`2.22, and 11.12]. Appropriate laboratory controls should be followed [ICH Q7, Sections 11.10, 16.10]
`regardless of who performs the testing.
`
`June 2015
`
`Can other departments outside of the
`uali
`unit be held resonsible for
`
`Yes. The quality unit is responsible for establishing a system to release or reject raw materials,
`intermediates, ackain, and labellin materials. This resonsibilit cannot be deleated [ICH Q7,
`
`Should GMP according to ICH Q7 be
`applied for manufacturing Steps
`before the defined ‘API
`starting
`rnaterial' i.e., Steps not identified in
`grey in Table 1?
`
`
`
`ICH Q7 does not apply to Steps prior to the introduction of the API starting material. However, there
`is an expectation that an appropriate level of controls suitable for the production of the API starting
`material should be applied [ICH Q7, Section 1.3].
`
`Normally, the ‘API-starting material’ is defined in the regulatory filing by the applicant and approved
`in the regulatory reviewing process. Additional guidance is provided to define and justify ‘API starting
`material’ derived from various sources [ICH Q11, Section 5]; for master cell banks, see [ICH QSB; ICH
`Q5D].
`
`June 2015
`
`June 2015
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`Dated: 10 June 2015
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`Q7 Q&As
`
`
`
`
`Section 2.22(2)]. The system established by the quality unit may allow ‘other departments’ to release
`releasing
`raw
`materials
`and
`intermediates?
`raw materials and intermediates (except intermediates that are for use outside the control of the
`manufacturer [ICH Q7, Section 2.22(l)] as long as oversight and the overall responsibility of this system
`remains with the uali
`unit.
`
`
`
`
`June 2015
`
`Does ICH Q7 expect that sampling
`be performed by the quality unit?
`
`What should be the frequency of a
`product quality review?
`
`June 2015
`
`No. ICH Q7 does not prescribe specifically who should perform the sampling [ICH Q7, Section 2.22].
`However, the quality unit has responsibility for reviewing and approving sampling plans [ICH Q7,
`Section 11.12] and procedures. Sampling should be performed by adequately trained personnel [ICH
`Q7, Section 3.10] and be appropriately documented as per [ICH Q7, Section 6.52].
`
`A product quality review is generally expected annually. Review timeframes can be appropriately
`adjusted based upon manufacturing and campaign duration with adequate justification. Even if no
`manufacturing has occurred in the review period, the quality review should be conducted as per section
`[ICH Q7, Section 2.50] and include stability, returns, complaints, and recalls.
`
`For example, a product quality review may encompass more or less than 12 months depending upon
`product campaign duration [ICH Q7, Section 2.50; ICH Q10, Section 2.6].
`
`
`Section 2.7, ICH Q7, Sections 2.2, 3.3].
`
`June 2015
`
`Should the product quality review of
`results include trend analysis?
`
`Trend analysis is usually an important element in verifying the consistency of the process as part of the
`product quality review [ICH Q7, Sections 2.50, 2.51]. Potential tools to use are described in [ICH Q9,
`Annex I.9].
`
`PERSONNEL
`
`June 2015
`
`June 2015
`
`What is the intent of the statement in
`
`‘training
`[ICH Q7, Section 3.12]
`should be periodically assessed’?
`
`Does ICH Q7 expect the use of a
`consultant
`and can a
`company
`delegate tasks and/or responsibility
`to a consultant?
`
`In [ICH Q7, Section 3.12], the statement ‘training should be periodically assessed’ refers to a system to
`evaluate ifpersonnel remain proficient and competent in their job tasks and responsibilities, and whether
`more frequent, additional, or new training is needed and recurring training is up to date.
`
`ICH Q7 does not expect the use of a consultant. Consultants may perform delegated tasks and/or
`provide advice. However, the ultimate responsibility for API quality must not be delegated [ICH Q10,
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`
`BUILDINGS AND FACILITIES — CONTAINMENT
`
`Dated: 10 June 2015
`
`Q7 Q&As
`
`
`
`ICH Q7 expects dedicated production areas for highly sensitising materials such as penicillins and
`cephalosporins because of the patient risk (e.g., anaphylactic shock to penicillin-allergic patients) from
`trace amounts of these compounds in other medicines [ICH Q7, Section 4.40].
`
`When are dedicated production areas
`expected?
`
`
`
`June 2015
`
`For materials of an infectious nature or high pharmacological activity or toxicity, a risk-based approach
`should be used to determine appropriate containment measures, which may include validated
`inactivation, cleaning and/or dedicated production areas [ICH Q7, Section 4.41].
`
`While ICH Q7 does not define high pharmacological activity or toxicity, these are generally determined
`by evaluating relevant animal and human data collected during research and development. Important
`considerations in this evaluation of pharmacological activity or toxicity may include Occupational
`Exposure Limit
`(OEL), Permitted Daily Exposure (PDE), Acceptable Daily Exposure (ADE),
`Threshold for Toxicological Concerns (TTC), No Observed Adverse Effect Level (NOAEL) [ICH S
`Guidelines, ICH EZE, Section 2.1.1], and the consequences of cross-contamination [ICH Q9, Section
`4.3].
`
`To what extent can quality risk
`The principles of quality risk management [ICH Q9, Annex II.4] should be applied to the design of
`management be used in establishing
`buildings, facilities and controls for the purpose of containment,
`taking into consideration the
`appropriate containment measures to
`pharmacological/toxicological/chemical/biological properties of the raw material, intermediate and/or
`API to be handled or manufactured.
`prevent cross-contarnination?
`
`June 2015
`
`Appropriate containment measures and controls [ICH Q7, Section 4.42] include but are not limited to
`the following:
`0
`Technical controls (e.g., dedicated production areas, closed/dedicated Heating Ventilation and Air
`Conditioning (HVAC) system, closed manufacturing systems, use of disposable technologies,
`design of facility and equipment for containment and ease of cleaning); and
`Procedural (organisational) controls (e.g., cleaning, personnel flow, environmental monitoring and
`training).
`Monitoring systems are important to check the effectiveness of the containment controls.
`
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`PROCESS EQUIPMENT — CLEANING
`
`Dated: 10 June 2015
`
`Q7 Q&As
`
`For dedicated equipment, is ‘visually
`clean’ acceptable for verification of
`cleaning
`effectiveness,
`(i.e.,
`no
`expectation for specific analytical
`determination)?
`
`‘Visually clean’ may be acceptable for dedicated equipment based on the ability to visually inspect and
`sufficient supporting data from cleaning studies (e.g., analytical determination to demonstrate cleaning
`effectiveness) [ICH Q7, Section 12.76]. Equipment should be cleaned at appropriate intervals (e.g.,
`time or number of batches) to prevent build-up and carryover of contaminants (e.g., degradants or
`objectionable levels of microorganisms) so that they do not adversely alter the quality of the API [ICH
`Q7, Sections 5.23, 12.7].
`
`for
`criteria
`acceptance
`Should
`residues be defined for dedicated
`
`equipment?
`
`Yes. Regardless of whether equipment is dedicated or not, it is expected that acceptance criteria for
`residues be defined and that the equipment be cleaned at appropriate intervals to prevent build-up and
`carry-over of contaminants. Intervals can be based on number of batches, product change-over, time,
`etc.
`[ICH Q7, Sections 5.22, 5.23, 5.24, 5.25, 8.50].
`
`June 2015
`
`June 2015
`
`June 2015
`
`Cleaning intervals and acceptance criteria should be established based on an understanding of the
`process/reactions/degradation, taking into account solubility, potency, toxicity, etc. Establishment of
`acceptance criteria does not necessarily imply sampling and testing after every cleaning. Visual
`inspection of equipment for cleanliness is an expectation of [ICH Q7, Section 5 .21]. Where validation
`data has confirmed effective cleaning, cleaning procedures should be monitored at appropriate intervals
`[ICH Q7, Section 12.76].
`
`Yes. Equipment cleaning is addressed in two sections in ICH Q7. While the cleaning validation [ICH
`Q7, Section 12.7] does not specifically address time limits for cleaning, [ICH Q7, Section 5.21] indicates
`that the maximum time between completion of processing and equipment cleaning (dirty hold time)
`should be established by the company. This maximum established dirty hold time is the time period for
`which evidence is available to demonstrate that the equipment can still be reliably cleaned. This
`maximum established dirty hold time is confirmed during the initial cleaning validation and can be
`extended with appropriate supporting data.
`
`While ICH Q7 does not specify the need for time limits between equipment cleaning and use in the next
`process (clean hold time), [ICH Q7, Section 5.21] does state that written procedures should include
`instructions for the protection of clean equipment from contamination prior to use and inspection of
`equipment for cleanliness immediately before use, if practicable.
`
`Yes. The cleaning validation section [ICH Q7, Section 12.7] does not specifically address campaign
`manufacture. However, sections [ICH Q7, Sections 5.23, 8.50] set forth the expectations that equipment
`
`equipment
`that
`expected
`it
`Is
`cleaning time limits be confirmed in
`cleaning validation?
`
`June 2015
`
`expected
`it
`Is
`manufacturing
`be
`cleaning validation?
`
`campaign
`that
`addressed
`in
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`
`of contaminants so that they do not adversely alter the quality of the API. The appropriate interval is
`confirmed during cleaning validation.
`
`process is not yet validated, both visual examination and analytical testing are expected.
`
`Jlllle 2015
`
`During cleaning
`A_t Pteduet _ehah8e0Ve1, are b_0th Appropriate cleaning validation verifies that the cleaning process is effective.
`Vlstlal
`eXa111111at1011 and ahalytleal
`validation, both visual examination and analytical testing shouldbe used to verify cleaning effectiveness
`testing heeessafy t0 Ve1'1fY that
`[ICH Q7, Sections 12.72 to 75]. Once the cleaning process is validated, routine monitoring of
`eq111P111e1'1t1s eleah?
`cleanliness of equipment at product changeover should include visual inspection [ICH Q7, Section
`12.76]. Frequency of analytical testing to verify ongoing effectiveness of the validated cleaning process
`is determined by the API manufacturer using a risk-based approach.
`In situations where the cleaning
`
`DOCUMENTATION AND RECORDS
`
`Dated: 10 June 2015
`
`Q7 Q&As
`
`
`What
`is meant
`bY ‘e0111P1et_e1Y
`For APIs with a retest date, [ICH Q7, Section 6.13] states that records related to production, control and
`d1st1'1b11ted’
`111
`[ICH Q7, Seet1011
`distribution should be retained for at least 3 years after the API batch is ‘completely distributed’, which
`5-13], Which states
`that
`‘1ee01ds
`is understood as the complete distribution of the entire batch of the API by the API manufacturer to the
`should be retained for at least 3 years
`next party in the supp1y chain
`after
`the
`batch
`is
`completely
`d1.stributed,,,
`
`In the case ofAPIs handled by agents, brokers, traders, distributors, repackers, and relabellers [ICH Q7,
`Section 17], ‘completely distributed’ refers to distribution of the received quantity of the batch of API.
`
`
`
`June 2015
`
`The intent of ICH Q7 is to retain records for the period of time that the API could be on the market in
`order to investigate any problems and/or product complaints. Based on accepted industry practice at
`the time ICH Q7 was written, it was not anticipated that a manufacturer would set a retest date longer
`than 3 years. However, the use of ‘at least three years’ in this section of ICH Q7 covers longer record
`retention periods, which is in alignment with the basic GMP principle and/or regional requirements that
`records be retained for the entire period the material is available on the market.
`
`It is good industry practice to consider retaining records for the period of time the drug product(s) in
`which the API was used may be available on the market.
`
`
`Does a batch 1111111be1111g system need No, [ICH Q7, Section 6.51] says only that batch production records should have a unique batch or ID
`to be sequential?
`number_
`
`June 2015
`
`Jlllle 2015
`
`Whe is responsible for the tssuahee
`efbateh PT0dt1et1011 Teeetds?
`
`[ICH Q7, Section 2.3] does not specify who is responsible for the issuance of batch production records
`[ICH Q7, Section 6.5] as long as the issuance process is described in writing and approved by the quality
`unit [ICH Q7 , Section 2.21].
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`
`MATERIALS MANAGEMENT
`
`Dated: 10 June 2015
`
`Q7 Q&As
`
`Does
`
`phrase
`the
`‘grouping of
`containers’ have the same meaning
`in [ICH Q7, Sections 7.20 and 7.24]?
`
`The phrase ‘grouping of containers’ should be read in the context of each sentence. A grouping of
`containers refers to multiple containers physically secured by the supplier (e.g., shrink-wrapped pallet,
`etc.) usually intended for ease of shipment and reconciliation.
`[ICH Q7, Section 7.20] is referring to
`incoming visual examination of materials before acceptance into the facility under quarantine.
`
`The phrase in [ICH Q7, Section 7.24], ‘grouping of containers (batches)’ contains an additional word
`‘batches’ because this section is addressing the need to establish batch traceability for the incoming
`material.
`
`expected in terms of
`is
`What
`evaluation of suppliers of materials?
`
`Different phrases are used to describe the expectation for evaluation of suppliers of materials [ICH Q7,
`Sections 7.11, 7.12, 7.31], including traders, if any.
`
`June 2015
`
`June 2015
`
`June 2015
`
`What is meant by ‘full analysis’ [ICH
`Q7, Section 7.31] on batches of raw
`materials to qualify a supplier?
`
`June 2015
`
`Are on-site audits required in the
`evaluation of suppliers?
`
`Which tests are considered to be
`
`June 2015
`
`identity tests?
`
`[ICH Q7, Section 7.12] states that all materials are purchased against a specification and from suppliers
`approved by the quality unit [ICH Q7, Section 7.31]. Prior to approval of any supplier, an evaluation
`should be conducted using a risk-based approach [ICH Q9, Appendix II.5; ICH Q7, Section 7 .3 1]. More
`extensive evaluation is needed for suppliers of those materials classified as ‘critical’ [ICH Q7, Section
`7.1 1].
`
`A ‘full analysis’ should include all tests specified by the user of the raw material in the regulatory filing.
`In cases where no filing is required, the full analysis should include tests in other formal written
`specifications issued by the user of the raw material [ICH Q7, 7.31]. A raw material supplier’s
`Certificate ofAnalysis (CoA) may not necessarily align with the user’s specifications.
`
`No. An on-site audit is not required; however, an on-site audit could be a useful tool in the evaluation
`of a supplier. A risk assessment of the material or the service provided can be used to develop an audit
`strategy and manage the ongoing evaluation of suppliers [ICH Q7, Sections 7.11, 7.31].
`
`For incoming production materials, identity tests and related methods should be used as described in
`the relevant sections of a Pharmacopoeia monograph, in an approved regulatory filing or in an in-house
`specification (including method/analytical procedure) [ICH Q7, Section 7.30]. When available, a
`discriminating test should be considered for identification testing. The visual examination of a label or
`the material is not considered sufficient except in the cases described in [ICH Q7, Section 7.32].
`
`June 2015
`
`Is it possible to extend the expiry date
`or retest date of a raw material and
`
`Manufacturing and labelling of raw materials for use by API manufacturers is outside the scope of ICH
`Q7. As such, retest and expiry dates, as defined in ICH Q7, do not strictly apply to raw materials and
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`Dated: 10 June 2015
`
`Q7 Q&As
`
`determine how long it may be
`extended for?
`
`may be used in a different manner by the raw material supplier. Expiry date, as defined in the glossary
`of [ICH Q7, Section 20], applies specifically to the API.
`
`raw materials are appropriate for the intended use at the time of use.
`
`API manufacturers may re-evaluate [ICH Q7, Section 7.5] and then use a raw material after the ‘expiry
`date’ or ‘retest date’, based on an appropriate scientific and risk-based justification (e.g., understanding
`of material attributes, testing, and stability). Similar justifications may be used to extend the date by
`which the material should be re-evaluated. It is the responsibility of the API manufacturer to ensure the
`
`PRODUCTION AND IN-PROCESS CONTROLS
`
`
`
`Can yield ranges defined for the first
`batch differ
`from latter batches
`
`June 2015
`
`within a campaign?
`
`June 2015
`
`is meant by ‘appropriate
`What
`specifications (of each batch) prior to
`blending’ [ICH Q7, Section 8.41]?
`
`Yes. Differing yield ranges [ICH Q7, Section 8.14] may be described and justified in the manufacturing
`procedure/master batch record explaining the ranges [ICH Q7, Section 6.41]. For example, the first
`batch in the series of production of batches of the same material (campaign) may leave residual material
`in the equipment, resulting in a low yield in the first batch and contributing to an increased yield in a
`subsequent batch of the campaign.
`
`As a principle, no batches with Out of Specification (OOS) results should be blended [ICH Q7 , Section
`8.41]. Blending is defined in [ICH Q7, Section 8.40].
`Individual intermediate and/or API batches
`should demonstrate conformance with the filed specifications prior to blending.
`In regions or
`circumstances where there are intermediates and/or APIs that do not require filing, conformance with
`the release specification should be demonstrated.
`
`PACKAGING AND IDENTIFICATION LABELLING OF APIS AND INTERMEDLATES
`
`NoQ&A.
`
`STORAGE AND DISTRIBUTION
`
`and if appropriate controls and documentation are in place’.
`
`June 2015
`
`is meant by
`What
`intermediates
`can be
`
`and
`‘APIS
`transferred
`
`under quarantine to another unit
`
`[ICH Q7, Section 10.20] states ‘APIS and intermediates should only be released for distribution to third
`parties after they have been released by the quality unit(s). APIS and intermediates can be transferred
`under quarantine to another unit under the company’s control when authorised by the quality unit(s)
`
` P. 11
`
`UT Ex. 2034
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`

`
`Dated: 10 June 2015
`
`Q7 Q&As
`
`The second sentence in [ICH Q7, Section 10.20] describes transport situations that are not considered
`distribution.
`It provides for physical movement (transfer but not release) of quarantined material to
`another unit. This unit can be on the same site, different site (within the same company), or a contract
`manufacturer (see final paragraph below).
`
`The goal of transfer under quarantine is to allow transportation and testing in parallel. Material that is
`transferred under quarantine is not to be used for further processing until all testing and quality review
`is complete and the material is released by the quality unit as defined in [ICH Q7, Section 2.22].
`
`This provision for transfer under quarantine is included in ICH Q7 for situations where a company is
`shipping APIs or intermediates from one unit to another and has both the need to expedite the shipping
`and the material management system in place to prevent use of the material before fi1ll release.
`Examples of circumstances where transfer under quarantine may be needed include extraordinary
`supply chain requirement(s) (e.g., short shelf-life), and materials with a lengthy timeframe for required
`test(s) (e.g., some microbiological tests, etc.).
`
`With appropriate oversight as described in [ICH Q10, Section 2.7], including a written agreement as
`described in [ICH Q7, Section 16.12], and appropriate ongoing controls, a contract manufacturer may
`be considered a ‘unit under the company’s control’. There is a joint responsibility by both parties to
`clearly justify and document the need to transfer the unreleased intermediate or API, and to ensure
`appropriate control is maintained to prevent use before full release.
`
`In cases where the API itself is the extract from an herbal or animal tissue preparation, all constituents
`of this extract (concomitant constituents) might be considered to be part of the API. Therefore, a
`production process-related impurity profile (except, for example, solvents used in the process), would
`generally not be expected. However, for all APIs derived from herbal or animal sources, tests and limits
`for possible contaminants originating from these sources (e.g., pesticides, mycotoxins, viruses,
`herbicides, elemental impurities and wrong species) should be established, based on a risk assessment.
`
`In cases where herbal or animal sources provide material that is further processed to yield a chemically-
`defined API, all constituents other than the API are considered impurities.
`In this situation, the API
`manufacturer would be expected to establish an impurity profile as well as an API release specification
`that would include impurity limits.
`
`and is this applicable to contract
`manufacturers?
`
`LABORATORY CONTROLS
`
`
`
`expected in terms of
`is
`What
`impurities for APIs extracted from
`herbal or animal tissue origin [ICH
`Q7, Section 11.2]?
`
`
`
`June 2015
`
` P. 12
`
`UT Ex. 2034
`SteadyMed v. United Therapeutics
`IPR2016-00006